sdii 42 phy polycystic ovary syndrome

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
http://www.stilverlangen.com/aandoeningen/pcos.php


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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
http://www.stilverlangen.com/aandoeningen/pcos.php


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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.shtml


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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.htm


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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.htm


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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.
http://tabeebe.com/mag/modules.php?name=Surveys&pollID=2


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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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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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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
http://images.search.yahoo.com/search/images/view?back=http%2525253A%2525252F%2525252Fimages.search.yahoo.com%2525252Fsearch%2525252Fimages%2525253Fp%2525253Dendometrial%2525252Bcancer%25252526ei%2525253DUTF-8%25252526x%2525253Dwrt&w=337&h=216&imgurl=www.monografias.com%2525252Ftrabajos26%2525252Fcarcinoma-endometrio%2525252FImage467.jpg&rurl=http%2525253A%2525252F%2525252Fwww.monografias.com%2525252Fcgi-bin%2525252Fjump.cgi%2525253FID%2525253D106714&size=31.2kB&name=Image467.jpg&p=endometrial+cancer&type=jpeg&no=1&tt=756&oid=437aa946410740fa&ei=UTF-8


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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

sdii 42 phy polycystic ovary syndrome

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