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7/30/2019 SDII 42 Phy Polycystic Ovary Syndrome
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Polycystic Ovary
SyndromeJennifer L. Phy, D.O.
Reproductive Endocrinology
& Infertility
Assistant Professor, TTUHSC
Department of Obstetrics and Gynecology
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Objectives
Review the importance and history ofpolycystic ovary syndrome (PCOS)
Describe the features and diagnostic criteriaof PCOS
Identify serious health conditions related to
or mimicking PCOS Review treatment options for PCOS
(fertility and general health)
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Why is Polycystic Ovary Syndrome (PCOS)
Important To Me As A Future Physician?
A patient with PCOS may present to..
a gynecologist reporting irregular periods
a primary care provider complaining of unexplainedweight gain
a dermatologist reporting acne, facial hair growth and loss
of hair on the scalp
an oncologist with diagnosis of uterine cancer
a medical endocrinologist with diabetes
a reproductive endocrinologist frustrated by infertility
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History of PCOS
In 1935, two gynecologists, Irving F. Stein andMichael L. Leventhal, described a symptomcomplex associated with anovulation
They described 7 patients (4 of whom wereobese) with amenorrhea, hirsutism and enlarged
polycystic ovaries
They performed bilateral wedge resection,removing one-half to three-fourths of each ovary
All 7 resumed normal menses and 2 becamepregnant
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Polycystic Ovarycount 10 bubbles = abnormal
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Polycystic Ovary Syndrome
PCOS is common
Affects 4-6% of reproductive age women
Cause is unknown but autosomal-dominant mode
of inheritance is suggested Characterized by
Oligoovulation (menses >35 day intervals)
Hyperandrogenism (hirsutism, acne, alopecia or
elevated serum androgens) Typically, patients have polycystic-appearing ovaries
by ultrasound
Reproductive and metabolic abnormalities are very
common
cycle day 1 to cycle day 1
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Diagnosis of PCOS
Easy or Not Easy? Combination of clinical and laboratory findings
Oligoovulation (menses >35 days apart)
Hyperandrogenism (clinical or laboratory) Exclusion of other conditions that may have similar
clinical features such as
Abnormal thyroid function (Check TSH)
Hyperprolactinemia (Check Prolactin) Congenital adrenal hyperplasia (Check 17-OHP)
Cushings syndrome (24-hour urine cortisol when clinically
indicated)
checking 21 OHase
deficiency
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Diagnostic Schemes for PCOS
Signs & Symptoms
National Institutes
of Health Criteria,
2013
(2 out of 3 are
required)
Rotterdam
Consensus
Criteria, 2003
(2 out of 3 are
required)
Androgen Excess
Society, 2006
(hyperandrogenism
plus one are
required)
Hyperandrogenism Possible but not
required
Possible but not
required
Required
Oligomenorrhea or
Amenorrhea
Possible but not
required
Possible but not
required
Possible but not
required
Polycystic ovaries
by ultrasound
diagnosis
Possible but not
required
Possible but not
required
Possible but not
required
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Oligoovulation
Menses >35 day intervals (from first day ofmenses from one cycle until the first day ofmenses of the next cycle)
May be assessed by patient history
A serum progesterone level does not need to bedrawn to prove anovulation or oligoovulation
Note that patients may have more frequentbreakthrough bleeding, especially if endometriallining is thickened (due to chronic estrogenexposure) can still bleed with oligoovulation
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Hyperandrogenism
Hirsutism
Acne
Alopecia (male pattern hair loss)
Elevated serum androgens
Total testosterone (*Most helpful androgen assay)
Free testosterone (Usually recognized clinically) Dehydroepiandrosterone sulfate (DHEAS) not
usually performed because of significant assay
variability
unnecessary
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Hirsutism
Excessive facial and
body hair growth
caused by excessandrogen production
Usually associated
with anovulatory
ovaries and loss ofcyclic menstrual
function
http://www.keratin.com/ah/ah010.shtml7/30/2019 SDII 42 Phy Polycystic Ovary Syndrome
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Factors Influencing Hair
Growth
Dermal papilla
Sexual hair Responds to sex steroids
Face, lower abdomen, anterior thighs, chest,
breasts
changes in hair FOLLICLE
http://www.tgfolk.net/sites/gtg/tfb-elect.htmlhttp://www.nevdgp.org.au/ginf2/murtagh/womens/Hirsutism.htm7/30/2019 SDII 42 Phy Polycystic Ovary Syndrome
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Androgenic Stimulation of the
Hair Follicle Requires conversion of testosterone to
dihydrotestosterone (DHT) in the hair
follicle
The sensitivity of the hair follicle to
androgens is determined by the local level
of 5-reductase activity
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5-Reductase Activity
Stimulated by insulin-like growth factor-I
(IGF-I)
IGF-I activity can intensify the hirsuteresponse in anovulatory women with
insulin resistance
IGF-1 sensitizes insulin receptor; insulin resistance > higher levels
of IGF-1
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Testosterone
80% of circulating testosterone is bound toa beta globulin - sex steroid hormone-
binding globulin (SHBG)Normally, approximately 1% of
testosterone remains unbound or free inwomen
Testosterone is produced in excess by theovarian theca cells in PCOS
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Testosterone
Plasma testosterone levels (normal 20 80 ng/dL)are elevated in approximately 70% of womenwith anovulation and hirsutism
Measurement may be inaccurate and costly
If the testosterone level exceeds 200 ng/dL, anandrogen-producing tumor must be suspected
Note that testosterone levels may be significantlyelevated in normal pregnancy (100 ng/dL in thefirst trimester and up to 800 ng/dL at term)
but still want to do it to rule out
ectopic testosterone
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Testosterone Levels in Hirsute
Women SHBG depressed by
excess androgens
SHBG depressed by
hyperinsulinemia (if
present)
Free testosterone elevated
Metabolic clearance rateof testosterone is
increased
http://images.search.yahoo.com/search/images/view?back=http%2525253A%2525252F%2525252Fimages.search.yahoo.com%2525252Fsearch%2525252Fimages%2525253Fei%2525253DUTF-8%25252526fr%2525253D%25252526fr2%2525253Dsfp%25252526p%2525253Dhirsutism&w=131&h=202&imgurl=hairgrowth.biz%2525252Fhirsutism-and-hypertrichosis%2525252Fbpp-generated%2525252Fscan0001b_folderthumb.jpg&rurl=http%2525253A%2525252F%2525252Fhairgrowth.biz%2525252F&size=7.7kB&name=scan0001b_folderthumb.jpg&p=hirsutism&type=jpeg&no=1&tt=499&oid=f2481ac4a2868c2c&ei=UTF-8http://www.endocrinolog.ru/illnesses/hirsutism/hirsutism_about.htm7/30/2019 SDII 42 Phy Polycystic Ovary Syndrome
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Can a hirsute woman have a
normal total testosterone
concentration?
yes; meta o c c earance o testosterone. tota testosterone test = ru es out
androgen secreting tumor but not PCOS.
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Can a hirsute woman have a normal
total testosterone concentration?
YES!
An elevated serum testosterone level is not mandatory forthe diagnosis of PCOS if clinical features of
hyperandrogenism are present.
The purpose of the testosterone level is to screen for an
androgen-secreting neoplasm.
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Androgen-producing tumors
One of medicines vastly overrated problems
Incredibly rare
Functioning ovarian tumors are almost alwaysPALPABLE (>5 cm)
If a tumor is suspected but not palpable,
catheterization procedures or surgical exploration
with bivalving of the ovaries may be necessary
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Androgen-producing tumors
Rapidity of development is important in
your evaluation
A woman who develops new onset ofhirsutism after age 25 and demonstrates
very rapid progression or masculinization
over several months to a year usually hasan androgen-producing tumor rather than
PCOS (Favorite Board Question)PCOS more gradual
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DHEAS Level
Dehydroepiandrosterone sulfate (DHEAS)circulates in higher concentration than any othersteroid and is derived almost exclusively from theadrenal gland
Laboratory ranges vary
Contributes to hirsutism by serving as aprehormone in hair follicles as a substrate for
androgen synthesis Often mildly elevated in PCOS
>700 ug/dL indicates abnormal adrenal function;however, this is so rare that its clinical use is
questioned
this test is expensive; usually not recommended to order
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17-hydroxyprogesterone
(17-OHP) Level Due to the relative frequency of late-onset adrenal
hyperplasia, routine screening of 17-OHP inwomen who complain of hirsutism isrecommended
Baseline 17-OHP should be measured in themorning and should be < 200 ng/dL
Levels between 200 and 800 ng/dL requireAdrenocorticotropin hormone (ACTH) testing(levels >800 ng/dL are virtually diagnostic of 21-hydroxylase deficiency)
Testing in the follicular phase of the menstrual cycle is best
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ACTH Stimulation Test
If baseline 17-OHP is > 200 ng/dL, the ACTHstimulation test is recommended
Synthetic ACTH (Cortrosyn) 250ug isadministered intravenously at 8:00 a.m.
17-OHP is measured at time 0 and at 1 hour
The 1-hour values are plotted to determine whetherthe patient is normal, a heterozygote or has lateonset congenital adrenal hyperplasia
expensive
on t nee a t e eta s ut now pr nc p es o t s; now norma va ues an outcomes o
tests (next step)
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Risk of Endometrial Cancer
Chronic anovulation (essentially a state of
unopposed estrogen) increases risk of
endometrial hyperplasia and endometrialcancer
If prolonged amenorrhea or endometrial
lining thickness is > 12mm, endometrialbiopsy is recommended (after confirming a
negative pregnancy test)
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Abnormal Endometrium
endometrial lining should be less than 10mm; this pt. is 40mm
PCOS: constant estrogen bombardment so endometrium keeps getting thicker
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Metabolic Disorders
Women with PCOS are at increased risk of
hyperinsulinemia, hyperlipidemia and
cardiovascular disease Anovulatory, hyperinsulinemic women are at a 5-
to 10-fold greater risk for noninsulin-dependent
diabetes
The age of onset of noninsulin-dependent
diabetes is about 30 years earlier than in the
general population
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Assessing Insulin Secretion
Hyperandrogenism and hyperinsulinemia are
commonly associated
Hyperinsulinemia can directly augment theca cellandrogen production in the ovary
Hyperinsulinemia contributes to
hyperandrogenism by inhibiting hepatic synthesis
of SHBG and decreasing insulin-like growth
factor binding protein-1 (ultimately increasing
free testosterone levels)
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Assessing Insulin Secretion
Anovulatory women who are
hyperandrogenic may be assessed for
glucose tolerance and insulin resistancewith measurement of 2-hour glucose and
insulin levels after a 75-g glucose load
Annual assessment is appropriate in womenwho continue to be overweight
gold standard
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Assessing Insulin Secretion
75 gm 2-hour oral glucose tolerance test:
Normal glucose or = 200 mg/dLInsulin responses 2 hours after glucose load:
Insulin resistance likely 100-150 uU/mL Insulin resistance 151-300 uU/mL Severe insulin resistance > 300 uU/mL
non-pregnant pts.
INS should never go over 100 in normal pts.
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Treatment of PCOS
Depends upon the goal of treatment
Menstrual cycle regulation
Weight loss and health improvement
Fertility
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When is use of metformin
appropriate for women withPCOS?
Metformin is an insulin-sensitizer commonly usedto treat noninsulin-dependent diabetes
Use of metformin is often used when insulinresistance is documented by glucose tolerance
testing Use of metformin for ovulation induction or to
improve response to clomiphene citrate (Clomid)is controversial
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Pregnancy in Polycystic Ovary
Syndrome (PPCOS) Study Recent randomized, multicenter, double-
blind study to evaluate ovulation induction
and live birth rates comparingMetformin/placebo
Clomiphene citrate/placebo
Combination of metformin/Clomiphene citrateIn the treatment of women with PCOS
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PPCOS Study
626 women with PCOS
Age 18-39 years
Randomized equally to the three treatment arms Treated for 6 cycles or for 6 months
Frequent serum progesterone levels were obtained
to determine ovulation Medications were discontinued when the patient
had a positive pregnancy test
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PPCOS Study Results
Live birth rate
Clomiphene citrate arm was 22.5% (47/209)
Metformin arm was 7.2% (15/208)
Clomiphene citrate/Metformin arm was 26.8%
(56/209)
Stratifying by BMI did not alter results
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PPCOS Study Results
There were no significant differences in
spontaneous abortion rates between groups
However, the spontaneous abortion ratewas highest in the metformin group 5/24
(20.8%) compared to clomiphene citrate
5/60 (8.3%) and combined therapy 7/76(9.2%)
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PPCOS Study Conclusion
Clomiphine citrate is superior to metformin
in achieving a live birth in infertile women
with PCOS There is no statistically significant
advantage to combined therapy in
achieving live birth
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Treatment of PCOS for menstrual
cycle control and hirsutism If conception is not desired, treatment is
directed toward optimizing health and
menstrual cycle control Diet and exercise
Metformin if indicated
Oral contraceptive pills (OCPs) Spironolactone if hirsutism is significant or
not improved with OCPs
always before medication treatment
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Treatment of PCOS/Hirsutism
Initial treatment:
Low-dose oral contraceptives
Suppress ovulation and LH production Increase SHBG
Progestins inhibit 5-reductase activity
Popular choices include triphasic preparations or
those containing drospirenone
Clinical improvement is slow
Benefits may take 6 months to detect clinically
m m c natura ormone cyc es
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Treatment of Hirsutism
Electrolysis or laser hair removal is not
recommended until hormonal treatment has been
used at least 6 months Spironolactone (aldosterone antagonist diuretic)
beginning 100mg daily
Inhibits adrenal and ovarian biosynthesis of androgens
Competes for androgen receptors at the hair follicle
Directly inhibits 5-reductase activity
Use of contraception is important
synergistic with OCPs; always use with OCPs.
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Typical Case
26 yo G0 desires conception
Menses occur every 2 to 6 months
Hirsutism, acne, elevated BMI
Normal pelvic exam (speculum, bimanual)
Husband has previously fathered a
pregnancy and has no health problems
How would you evaluate?total testosterone test, 17-OHP, TSH, prolactin.
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Evaluation for PCOS
Detailed history and physical
Quantitative beta-hCG
TSH Prolactin
Total testosterone
17-OHP
Lipid panel
2-hour 75 gm glucose tolerance test
also ultrasound (>10 follicles); >12mm = biopsy it.
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Case Results Quantitative beta-hCG negative
TSH and prolactin are normal
Total testosterone elevated (80 ng/dL)
17-OHP normal (
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Case
Diagnosis:
Polycystic ovary syndrome (PCOS)
Treatment
Preconception counseling Prenatal vitamins
Emphasize importance of diet and exercise
Good candidate for clomiphene citrate (Clomid) 50 mgdaily, menstrual cycle days 3 7
Consider metformin (especially if abnormal 2 hour oralglucose tolerance test)
Timed intercourse or insemination
Consider checking ovulation predictor kit and cycle day
21 progesterone to confirm ovulation
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Ovulation induction
Goal to achieve ovulation with lowest requireddose of medication
Clomiphene citrate
Letrozole (less common)
Possibly in combination with metformin
Well-tolerated
Simple Inexpensive
Multiple birth risk (reported 5-15%)
can make them grumpy; headaches, visual changes
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Clomiphene citrate (Clomid) Use lowest dose possible to achieve ovulation (50
mg, 100 mg, 150 mg)
Side effects include moodiness and rarelyheadaches and visual changes
Monitor for ovulation via ovulation predictor kit orcycle day 21 progesterone (>3 ng/mL)
Cyst formation is common
Site of action: Hypothalamus
Maximum of 12 cycles per lifetime is generallyaccepted
ant -an rogen t at acts at ypot a amus
mimics low estrogen = FSH/LH surge
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Summary
Proper evaluation and management of PCOSbegins with a careful history and physicalexamination
Laboratory evaluations are important to detectpotentially serious medical conditions associatedwith hirsutism and anovulation
Medical therapy requires patience
Proper management of PCOS can be veryrewarding and can restore a patients health,fertility, self-esteem and happiness
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Questions?
nuns g rate o ecause no s.
chickens ovulate every day = high risk of ovarian cancer.
OCP decrease risk
for ovarian cancer.
pandas ovulate every 2 years = low risk