Ahmad O. Hammoud MD, MPHAssistant Professor Obstetrics and GynecologyReproductive Endocrinology and

InfertilityUniversity of Utah

Medical DirectorUtah Center for Reproductive Medicine (www.utahfertilitycenter.com)

Polycystic ovarian syndrome

Case

A 32-year-old woman was evaluated because of oligomenorrhea and difficulty becoming pregnant

Menarche had occurred at 12 years of age and menses were regular until the patient began taking oral contraceptives at 20 years

of age

Case

At 25 years of age, she discontinued oral contraceptives and irregular menstrual cycles developed, ranging from 31 to 51 days, with menstrual flow of 7 days' duration.

Between the ages of 28 and 32 years, she had unprotected coitus with her husband but did not conceive

She reported frequent acne and facial hair that she removed manually

Positive elements

Young women Irregular periodsInability to conceive Acne and increased facial hair

Polycystic ovarian syndromeIn 1935, Stein and Leventhal published a paper

on their findings in seven women with AmenorrheaHirsutism ObesityCharacteristic polycystic appearance of the

ovaries

The most common reproductive endocrinopathy of women during their childbearing years: 4% to 8%

Consensus on diagnostic criteria for PCOS

Rotterdam 2003 criteria 2/3

1. Oligo- and/or anovulation

2. Clinical and/or biochemical signs of hyperandrogenism

3. Polycystic ovaries on ultrasound

4. Exclusion of other etiologies

ESHRE and ASRM 2003

1992 NIH criteria 1 and 2

1. Chronic anovulation

2. Clinical and/or biochemical signs of hyperandrogenism

3. Exclusion of other etiologies

NIH,1992

Consensus on diagnostic criteria for PCOSThe 2003 criteria introduced the “Non-NIH

PCOS”Hyperandrogenism but ovulatoryNon hyperadrogenic with anovulation

Criteria NIH PCOS Non-NIH PCOS

Anovulation + + +

Hyperandrogenism

+ + +

PCO + + +

Consensus on diagnostic criteria for PCOSAndrogen Excess Society Guidelines 2006:PCOS is a hyperandrogenic disorder:

Hirsutism or elevated free testosterone andPCO morphology 75% or Ovulatory dysfunction

Exclusion of other etiologies

Azziz et al, JCEM, 2006

Consensus on diagnostic criteria for PCOS

Rotterdam criteria

Criteria NIH PCOS Non-NIH PCOS

Anovulation + + +

Hyperandrogenism

+ + +

PCO + + +

Androgen Excess Society

Menstrual dysfunction

Oligomenorrhea fewer than nine menses per year or amenorrhea

Anovulatory cycles may lead :Dysfunctional uterine bleeding Decreased fertilityEndometrial hyperplasia

Usually start at menarche and the postpubertal phase

Hyperandrogenism

Clinical hyperandrogenism:Hirsutism: excessive growth of terminal hair

in women in a male like pattern

Acne 10 -15%

Alopecia: weak marker unless associated with anovulation 5%

Modified Ferriman-Gallwey scoring

Androgen Excess and PCOS Society

Hirsutism

Visual scoring: modified Ferriman-Gallawey score 6-8

50% of women with unwanted hair score< 5 had PCOS

Less prevalent in East Asian or in adolescence

Souter et al , Am J Obstet Gynecol. 2004

Hyperandrogenism

Biochemical hyperandrogenism Total Testosterone is not a sensitive marker Free testosterone T: equilibrium dialysis or

calculated:

Isolated elevations in DHEA-S 10% or elevated Androstenedione 10%

20-40% will have normal androgens.

Ultrasonographic Polycystic ovaries

Ultrasonographic Polycystic ovaries

Ultrasonographic Polycystic ovariesPresence of 12 or more follicles in each ovary

measuring 2 ± 9 mm orIncreased ovarian volume >10 ml

PCO is present in 75% of women with PCOS

PCO is present in 22% of women in the general population

Azziz et al, JCEM, 2006

Farquhar el al, Aust N Z Obstet Gynecol 1994

Ultrasonographic Polycystic ovariesThis definition does not apply to women taking

OCP

Only one ovary fitting this definition is sufficient

If there is a dominant follicle >10 mm or a corpus luteum, the scan should be repeated the next cycle

The presence of an abnormal cyst or ovarian asymmetry necessitates further investigation

Other manifestation Acanthosis nigricans is common in obese PCOS

neckaxillaarea beneath the breasts Intertrigenous areaselbows and knuckles

Women with PCOS may experience increased skin oiliness resulting from excessive stimulation of the pilosebaceous unit by increased androgen production

Case

What about our patient:

1-Irregular periods2-Clinical hyperandrogenism3-No ultrasound

She may have PCOS if there is no other abnormalities.

UK, n = 1741 USA,n= 398

Obesity•Obesity : 50% PCOS

•Increased waist-to-hip ratio, or ‘‘android’’

Insulin resistance

Insulin resistance: 50% in obese and non obese

A defect in the insulin signaling pathway in muscle and adipose tissue

No validated clinical test

  IFG IGT  Diabetes 

Fasting glucose 

≥110 to 125 ≥126 

2-hour glucose

≥140 and <200 ≥200 

HbA1 C ≥6.5

Random glucose

>200 with symptoms

ADA criteria for the diagnosis of diabetes mellitus, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG)

LH and LH/FSH ratio

Both the absolute level of circulating LH and its relationship to FSH levels are significantly elevated in PCOS

LH levels should not be considered necessary for the clinical diagnosis of PCOS

Useful as a secondary parameter especially in lean women with amenorrhea, or in research

Exclusion of related disorders

Initial work-up may also include :FSH and estradiol E2 : hypogonadotropic

hypogonadism or premature ovarian failure

Prolactin to exclude hyperprolactinemia NB: many hyperandrogenic patients may

have prolactin levels slightly above normal

TSH: exclude hypothyroidism

Exclusion of related disorders

Non-classic adrenal hyperplasia Basal morning 17-hydroxyprogesterone Cut-off values 2 and 3 ng/mlValues in excess of 3 ng/mL warrant further evaluation by

an ACTH stimulation test

Cushings syndrome: 24-hour urinary free cortisol A value in excess of 3 times the normal assumes the

diagnosisIntermediate values warrant a repeat of the test

Exclusion of related disorders

Ovarian hyperthecosisObese and exhibit acanthosis nigricans , severe Hirsutism,

virilizing signsNests of luteinized theca cells scattered throughout the stroma The ovary is enlarged and of an extremely firm texture The absence of follicle formation High serum androgen concentrations

Syndromes of severe insulin resistance (e.g. for the diagnosis of the hyperandrogenic insulin-resistant acanthosis nigricans or HAIRAN syndrome)

Exclusion of related disordersAndrogen-secreting neoplasm

May arise from the ovary and the adrenal glandBest predictor is clinical presentation Total T and DHEA-S . Neoplasm should be considered if testosterone >200 ng/dL

and DHEA-S >700 ng/ mL High dose exogenous androgens

Case

Test to order on our patient:Pelvic ultrasound FSH, Estradiol day 3 of cycleProlactin, TSH 17 OH progesterone, free and

totalTestosterone, DHEAS if severe or rapid hirsutism.

Lipid profile and 2 hour glucose tolerance test

Pathogenesis

Cardiovascular

Hypertension

Develops in some women with the polycystic ovary

syndrome during their reproductive years

Reduced vascular compliance and vascular endothelial

dysfunction

Coronary and other vascular disease

Hypertriglyceridemia, increased levels of very low-

density lipoprotein and low-density lipoprotein

cholesterol, and decreased levels of high-density

lipoprotein cholesterol

Obstructive sleep apnea

Cannot be explained by obesity alone

The risk of sleep-disordered breathing was increased by a

factor of 30

Insulin resistance appears to be a stronger predictor of

sleep-disordered breathing than is age, body mass index,

or the circulating testosterone concentration

Association with cancer Increased prevalence of endometrial hyperplasia and

carcinoma Attributed to the persistent stimulation of endometrial

tissue by estrogen (mainly estrone) without the progesterone

Breast and ovarian cancer have been variably associated with the polycystic ovary syndrome

Criteria for the metabolic syndrome in women with PCOS

Case

InfertilityIrregular periods Hirsutism

Treatment

Insulin resistance and glucose intoleranceHirsutism and acneOligomenorrhea and amenorrheaOvulation Induction

First line therapy

Weight reduction is important in treating overweight patients

No unique weight-loss regimen targets excess adiposity specific to the syndrome: Hypocaloric diet

Modest reductions in body weight (2 to 7 percent) through lifestyle modification have been associated with reductions in androgen levels and improved ovulatory function

Metformin

Inhibit hepatic glucose production

Started at 500mg daily , titrating up to 500mg three time daily over 7-10 days.

Max 1000 mg BID

Outcome within 2-4 months

Metformin and weight reduction

Metformin vs placebo

Difference in BMI -0.04 (-0.29 - +0.22)

Tang et al, Cochrane Database Syst Rev. 2009

Metformin

Adverse effects :Nausea and diarrhea 10-15% of patientsLactic acidosis

Troglitazone: report of fatal liver toxicity

Pioglitazone: (Vs Placebo) little evidence of effect on any outcome , It does induce weight gain

Tang et al, Cochrane Database Syst Rev. 2009.

Hirsutism and acneOral Contraceptives:

Suppress LH and androgen production

Increase SHBG: reducing free testosterone

The choice of OCP is controversialLevonorgesterel and Norethindrone

Norgestimate and desogestrel

Drosperinone

Potential adverse effects on insulin resistance, glucose tolerance, vascular reactivity, and coagulability

Hirsutism and acne

Spironolactone: has moderate antiandrogenic effects : 100 to 200 mg daily.

Caution when used with drosperinoneAntiandrogens :

1. Cyproterone acetate competitively inhibits the binding of testosterone and 5a-dihydrotestosterone,

2. Flutamide is a potent nonsteroidal antiandrogen that is effective in the treatment of hirsutism. hepatocellular dysfunction

3. Finasteride inhibitor of type 2 5α reductase to treat hirsutism

Oligomenorrhea and amenorrhea

PCOS : 36% endometrial hyperplasia:25% cytologic atypia

Cyclic progestin or oral contraceptives

Endometrial biopsy in patients who have not had menstrual bleeding for 3 month or longer

Use of ultrasonography to determine endometrial thickness: 7mm

Ovulation induction: ClomipheneStart 50 mg daily on day 2 ,3,4 or 5 for five

daysIf failed , increased to 100 daily , followed

by 150 daily

Ovulation monitoringTemperature chartingSerum Progesteorne (day 21)LH kit Transvaginal ultrasound

Clomiphene: Step-up protocol

Hurst et al, Am J Obstet Gynecol. 2009

Clinical outcome60 – 85 % will ovulate30-40% will become pregnantCumulative pregnancy rate over 12 month:

70%

Hughes et al. Cochrane Database Sys Rev CD 000056, 2000

Clomiphene citrate

Clomid resistant patients

DexamethasoneLetrozole (Femara) or other aromatase

inhibitorsTamoxifen Gonadotropins

Legro et al, NEJM, 2007

Metformin: Ovulation induction

Laparoscopic ovarian drilling(LOD)Ovulation rate : 54 - 95% Pregnancy rates: 28 - 78 %Need for ovulation induction agent:

3-6 months17.5 - 22.6%

Failure rates: 20-30% ObeseHyperandrogenismInfertility of more than 3 years

Amer et al Hum Reprod 2004

Unlu C, Atabekoglu CS.Curr Opin Obstet Gynecol. 2006

LOD versus Gonadotropins

Odds ratio 95% CI

Ongoing pregnancy 1.08 0.69 - 1.71

Live birth 1.04 0.59 - 1.85

Miscarriage rate 0.81 0.36 - 1.86

Multiple pregnancy 0.13 0.03 - 0.52

Farquhar et al Cochrane Database Syst Rev. 2007

Case

Short term treatment :Diet and weight lossClomid ± Metfromin

Long term treatment Diet and weight lossMetforminOCP