Transcript Polycystic ovary syndrome (PCOS)

Polycystic Ovary Syndrome
PCOS
Talia Eldar-Geva, MD, PhD
Director Reproductive Endocrinology
and Genetics Unit, IVF Unit
Shaare-Zedek Medical Center
5th year Medical Students, 2014
‫אז מה זה??‬
“Stein-Leventhal Syndrome”
Stein, Leventhal. Am J Obstet Gynecol 1935:
Amenorrhea associated with bilateral
polycystic ovaries.
Seven women with amenorrhea, hirsutism,
obesity, and a characteristic polycystic
appearance of their ovaries.
Ovarian Morphology
Vaginal US
12 follicles of 2-9 mm in diameter in one
ovary and/or
ovarian volume > 10cm3
Hyperandrogenism
• Hirsutism
• Acne
• Male-pattern alopecia
Hirsutism
Ferriman-Gallwey scoring system
0-36
mild
Moderate
severe
Diagnostic criteria
ESHRE/ASRM PCOS Consensus
(Rotterdam, July 2003)
• Two out of three:
–Ovarian morphology
–Hyperandrogenism
(biochemical or clinical)
–Chronic Oligo/anovulation
Range of clinical manifestations
of PCOS
Mensrual disturbence
two thirds
Oligomenorrhoea
50%
Amenorrhoea
20%
Regular cycles
30%
Infertility
(~75% of anovulatory infertility)
Hyperandrogenism
50%
Obesity
Insulin resistance
30-75%
>50%
Asymptomatic
(20% of those with PCO)
Pathogenesis
• No single etiologic factor fully accounts for the
spectrum of abnormalities in PCOS
• GnRH pulse frequency
• Pituitary response
– LH LH/FSH
– stimulate androgens secretion by theca cells
• Cytochrome P-450c17
– ovarian theca cells of PCOS women are more efficient
at converting androgenic precursors to testosterone
than are normal theca cells.
• Insulin
• ?
SHBP
Weight increase
decreases
Genetic defects in
insulin action
INSULIN
increases
Insulin receptor
disorders
IGFBP-1
decreases
Free IGF-I
increases
THECA
LH
Free Testosterone
increases
Androstenedione
increases
+
Testosterone
increases
Free E2
increases
Acanthosis Nigricans
INSULIN RESISTANCE: DIAGNOSIS & SCREENING
•OGTT (75 gr)
– Glucose response, Insulin response
– area under curves
– Glucose Insulin (G:I) ratio
Fasting G:I ratio < 4.5 is the single best
screening measure for detecting
Insulin Resistance in PCOS
Differential Diagnosis
•
•
•
•
•
•
•
Hyperprolactinemia
Nonclassic congenital adrenal hyperplasia
Cushing’s syndrome
Androgen-secreting neoplasm
Acromegaly
Hypothyroidism
Drugs-related (androgens, valproic acid,
cyclosporine, or other drugs).
Hormones profile
• Testosterone
– SHBG
– Free Androgen Index
• LH
• LH/FSH
• Androstenedione
• DHEA-S
• 17-OH-Progesterone
• Lipids profile
• Glucose
• Insulin
Frequency:
5-10% of females
Dermatologist
Disorder of
hair growth,
Acne
Fertility problem
Menstrual
Gynecologyst dysfunction
?
Internist
Obesity problem
pseudo
Cushing’s disease
General
practitioner
TOPIC: Summary of Disease Risks
Increased risk very likely
• Type 2 diabetes mellitus
• Dyslipidemia
• Endometrial cancer
Increased risk possible
• Hypertension
• Cardiovascular disease
• Gestational diabetes
mellitus
• Pregnancy-induced
hypertension
Increased risk unlikely
• Ovarian cancer
• Breast ca.
Long-Term
Disease Risks
in PCOS
(Independent of
Obesity)
‫לו הייתם שטיין ולוונטל‬
‫איך הייתם מטפלים?‬
‫‪WEDGE RESECTION‬‬
Laparoscopic Ovarian “Drilling”/Cauterization
(Stein-Leventhal - wedge resection
‫הצגת מקרה‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫בת ‪ ,32‬וסת אחת ל ‪ 45-60‬ימים‪ ,‬וסת אחרון לפני ‪45‬‬
‫ימים‪.‬‬
‫משקל ‪ 82‬ק"ג‪ ,‬גובה ‪ 165‬ס"מ (‪ 31 BMI‬ק"ג‬
‫למ"ר)‪ ,‬עודף שיער בפנים‪.‬‬
‫‪ ,16IU/L=LH‬טסטוסטרון תקין‪.‬‬
‫אבל ‪– SHBG‬‬
‫נמוך‪ ,‬ולכן‪...‬‬
‫האם חסר משהו לאבחנה?‬
INDUCTION OF OVULATION
WHO Group II
PRINCIPLE - need stimulation with FSH
Clomiphene Citrate
HMG
FSH
- urinary
- recombinant
Pulsatile GnRH
(Ovarian cauterization)
Clomiphene citrate (CC)
(Ikaclomin, Clomid)
Synthesized 1956
Clinical use 1960
Approved (US) 1967
Orally active
Non-steroidal
Similar to estrogen
Estrogen agonist / antagonist
1-3 months in serum
CC: Mechanism of Action
PRINCIPLE: Weak ESRM (estrogen receptor modulator)
Binding to Hypothalamic Estrogen receptors
Occupying Estrogen-receptors for long time
Inhibition of receptor replenishment
“mimicking” hypoestrogenism
Increase in GnRH pulse frequency (& amplitude)
FSH & LH levels rise
Treatment cycle with CC
First step –
Progesterone
treatment
CC
50-200
mg/day
5 days
Progesterone
LH
FSH
5
9
Cycle days
induce bleeding–
decreases LH –
levels
opposes estrogen- –
induced
endometrial
hyperplasia
CC: Minor Effects
Directly stimulates FSH secretion from hypophysis
Direct ovarian effect
BUT
Anti-estrogenic effect in the
Cervix
Endometrium
Can induce/aggravate luteal-phase defect
Response to clomiphene
Ovulation
- no pregnancy
45%
No response
20%
Ovulation
& pregnancy
35%
Cumulative 6 cycles pregnancy (75%) rate approaches the normal rate (if no
other cause of infertility)
CC: Side Effects
10-20%
5.5%
2%
3%
1.5%
1.3%
0.3%
Vasomotor flushes
Abdominal bloating, pain
Breast discomfort
Nausea, vomiting
Visual symptoms
Headache
Dryness, loss of hair
•
•
•
•
•
•
•
CC: Complications
• Multiple pregnancy
• high-order
• OHSS
• mostly mild - moderate
8-10%
<1%
5-10%
• No or slightly increased ectopic pregnancy rate (1%)
• No change in miscarriage rate (15%)
• No change in congenital malformations rate
• Inconclusive data regarding increased cancer rate
What to do with CC failures?
•
•
•
•
•
•
•
Extended protocols
Add dexamethasone
Add pretreatment suppression (pill, GnRH-a)
Treat obesity
Treat hyperinsulinemia
Add intra-uterine insemination
Ovarian cauterization
• Estrogen to improve endometrial factor is ineffective
• Do not treat for more that 6 cycles
GONADOTROPINS
TREATMENT
• Human menopausal Gonadotropins (hMG)
– FSH 75IU + LH 75IU
• Urinary FSH - FSH 75IU, <1% LH
• Highly purified urinary FSH - < 0.1% LH
• Recombinant FSH
• hCG
• Recombinant LH
• Could be replaced by GnRH / GnRH agonist
Treatment Cycle with Menotropins
hCG, 5000-10000IU
FSH daily
US for follicular number and size
When follicle 17-20mm
and E2 600-1500pmol/L
US & E2 measurement
every 2 -5 days
225
150
75
5
+5-7
Cycle Days
+5
+5
Complications of Gonadotropins
Stimulation
• MULTIPLE FOLLICULOGENESIS
– MULTIPLE PREGNANCIES – 20%!
– OHSS – (severe 1-3%)
• HIGH MISCARRIAGE RATE (25%)
Low dose protocols
Step-down •
Step up •
Sequential •
step-up/stepdown
LOW DOSE FSH
The FSH threshold theory
37.5
37.5
14
7
DAYS
7
Low dose FSH
Monovulation
70%
Fecundity/cycle
20%
OHSS
<0.1%
Multiple pregnancies 6%
•
•
•
•
FSH or HMG in PCOS?
Recombinant or urinary FSH?
• Same pregnancy rates
• Same OHSS rates
• Same multiple pregnancy rate
OBESE PCOS - LOSS OF WEIGHT
Improves signs of hyperandrogenism
Induces/facilitates ovulation
Loss of >5% of body weight Reduces - insulin levels
- ovarian androgen
production
- circulating free
testosterone
Increases - SHBG, IGFBP-1
75% conceived
Insulin sensitizing agents
Metformin (Glucophage)
•
•
•
•
•
Inhibits hepatic glucose production.
Reduces insulin resistance and secretion.
Causes weigh loss.
Directly inhibits ovarian steroidogenesis.
Reduces T, free T, A4, DHEAS, LH,
Waist to hip ratio, BMI, BP.
• Increases FSH, SHBG
• Side effects - gastrointestinal (30%).
• 1500mg-2500mg/day, at least 3 months.
Metformin as adjuvant therapy for
induction of ovulation
• Restored menstruation and ovulation
• Improves ovulation rate with CC
• Metformin + FSH = fewer follicles, less
OHSS
• Improved quality of mature oocytes,
fertilization & pregnancy rates
Laparoscopic Ovarian “Drilling”/Cauterization
(Stein-Leventhal - wedge resection
Treatment sequence in
Weight loss / PCOS
change life stile
Clomiphene
Low dose FSH
?
Metformin (only if insulin
resistant/obese?)
GnRH-agonist (if LH very high)
Laparoscopic ovarian drilling