Polycystic ovarian syndrome
Ahmad O. Hammoud MD, MPH
Assistant Professor
Obstetrics and Gynecology
Reproductive Endocrinology and Infertility
University of Utah
Medical Director
Utah Center for Reproductive Medicine
(www.utahfertilitycenter.com)
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 periods
 Inability to conceive
 Acne and increased facial hair
Polycystic ovarian syndrome
 In 1935, Stein and Leventhal published a
paper on their findings in seven women with
 Amenorrhea
 Hirsutism
 Obesity
 Characteristic 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
1992 NIH criteria 1 and 2
1. Chronic anovulation
2. Clinical and/or
biochemical signs of
hyperandrogenism
3. Exclusion of other
etiologies
NIH,1992
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
Consensus on diagnostic criteria for
PCOS
The 2003 criteria introduced the “Non-NIH
PCOS”
 Hyperandrogenism but ovulatory
 Non hyperadrogenic with anovulation
Criteria
NIH PCOS
Anovulation
+
+
Hyperandrogenism
+
+
PCO
+
Non-NIH PCOS
+
+
+
+
Consensus on diagnostic criteria for
PCOS
Androgen Excess Society Guidelines 2006:
 PCOS is a hyperandrogenic disorder:
Hirsutism or elevated free testosterone and
 PCO morphology 75% or
 Ovulatory dysfunction
 Exclusion of other etiologies
Azziz et al, JCEM, 2006
Consensus on diagnostic criteria for
PCOS
Criteria
Anovulation
Rotterdam criteria
NIH PCOS
Non-NIH PCOS
+
+
+
Hyperandrogenism
+
PCO
+
+
+
+
Androgen Excess Society
+
Menstrual dysfunction
 Oligomenorrhea fewer than nine menses per
year or amenorrhea
 Anovulatory cycles may lead :
 Dysfunctional uterine bleeding
 Decreased fertility
 Endometrial 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
Souter et al , Am J Obstet Gynecol. 2004
 Less prevalent in East Asian or in
adolescence
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 ovaries
 Presence of 12 or more follicles in each ovary
measuring 2 ± 9 mm or
 Increased 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 ovaries
 This 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
 neck
 axilla
 area beneath the breasts
 Intertrigenous areas
 elbows 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 periods
 2-Clinical hyperandrogenism
 3-No ultrasound
 She may have PCOS if there is no other
abnormalities.
Obesity
•Obesity : 50% PCOS
•Increased waist-to-hip ratio, or ‘‘android’’
UK, n = 1741
USA,n= 398
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
ADA criteria for the diagnosis of diabetes mellitus,
impaired glucose tolerance (IGT), and impaired fasting
glucose (IFG)
IFG
Fasting
glucose
2-hour
glucose
HbA1 C
Random
glucose
IGT
≥110 to 125
Diabetes
≥126
≥140 and <200
≥200
≥6.5
>200 with
symptoms
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/ml
 Values 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
diagnosis
 Intermediate values warrant a repeat of the test
Exclusion of related disorders
 Ovarian hyperthecosis
 Obese and exhibit acanthosis nigricans , severe Hirsutism,
virilizing signs
 Nests 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 disorders
 Androgen-secreting neoplasm
 May arise from the ovary and the adrenal gland
 Best 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 cycle
 Prolactin, 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
 Infertility
 Irregular periods
 Hirsutism
Treatment
 Insulin resistance and glucose intolerance
 Hirsutism and acne
 Oligomenorrhea and amenorrhea
 Ovulation 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 patients
 Lactic 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 acne
Oral Contraceptives:
 Suppress LH and androgen production
 Increase SHBG: reducing free testosterone
 The choice of OCP is controversial

Levonorgesterel 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 drosperinone
Antiandrogens :

1.
2.
3.
Cyproterone acetate competitively inhibits the binding of
testosterone and 5a-dihydrotestosterone,
Flutamide is a potent nonsteroidal antiandrogen that is
effective in the treatment of hirsutism. hepatocellular
dysfunction
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: Clomiphene
 Start 50 mg daily on day 2 ,3,4 or 5 for five
days
 If failed , increased to 100 daily , followed by
150 daily
 Ovulation monitoring
 Temperature charting
 Serum Progesteorne (day 21)
 LH kit
 Transvaginal ultrasound
Clomiphene: Step-up protocol
Hurst et al, Am J Obstet Gynecol. 2009
Clomiphene citrate
 Clinical outcome
 60 – 85 % will ovulate
 30-40% will become pregnant
 Cumulative pregnancy rate over 12 month:
70%
Hughes et al. Cochrane Database Sys Rev CD 000056, 2000
Clomid resistant patients
 Dexamethasone
 Letrozole (Femara) or other aromatase
inhibitors
 Tamoxifen
 Gonadotropins
Metformin: Ovulation induction
Legro et al, NEJM, 2007
Laparoscopic ovarian drilling(LOD)
 Ovulation rate : 54 - 95%
 Pregnancy rates: 28 - 78 %
 Need for ovulation induction agent:
 3-6 months
 17.5 - 22.6%
 Failure rates: 20-30%
 Obese
 Hyperandrogenism
 Infertility of more than 3 years
Unlu C, Atabekoglu CS.Curr Opin Obstet Gynecol. 2006
Amer et al Hum Reprod 2004
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 loss
 Clomid ± Metfromin
 Long term treatment
 Diet and weight loss
 Metformin
 OCP