Polycystic ovarian syndrome - American Association of Diabetes
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Transcript Polycystic ovarian syndrome - American Association of Diabetes
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