Polycystic Ovary Syndrome (PCOS)

Objectives
Describe PCOS and associated pathophysiology
Identify risk factors of and conditions related to PCOS
Diagnose and evaluate comorbidities relevant to PCOS
Characterize goal specific therapy options
PCOS
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Polycystic Ovary SYNDROME
1800s: polycystic ovaries
“cystic oophoritis”; “sclerocystic”
Stein & Leventhal (1953)
Enlarged ovaries, hirsutism, obesity, and chronic anovulation
“Syndrome O”
Ovarian confusion
Ovulation disruption
Over‐nourishment
Overproduction of insulin
PCOS
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PCOS
PCOS
Collection of signs and symptoms
May be difficult to diagnose
Heterogeneous presentation
Features change with age
NO single test or feature is diagnostic

PCOS: Clinical Presentation Signs and Symptoms
PCOS

Epidemiology
PCOS
Most common endocrine abnormality in reproductive aged women
5‐15% women affected – with ethnic predilection
Caucasians:
Latina/hispanics:
African americans:
4.8%
13%
8.0%
Hereditary:
Affected mother 35%
Affected sister 40%

Polycystic Ovary Syndrome (PCOS)
ETIOLOGY & PATHOPHYSIOLOGY
PCOS

PCOS: Etiology
PCOS
Neuroendocrine derangement: ↑LH relative to FSH
Hyperinsulinemia: defect in insulin action or secretion
Androgen excess: ovarian and adrenal

Normal Menstrual Cycle
PCOS
LH
FSH
PCOS
Cycle day
Cycle day

Effects of Hyperinsulinemia
Decrease binding proteins (ie., SHBG, IGFBP‐I)
Increase unbound androgens
Reduce HDL [good] cholesterol
Risk for PCOS (Legro et al.,1999; Dunaif, et al. 1997)
Insulin resistance: ~50%
NIDDM: 8%
Acanthosis nigricans
PCOS

PCOS: Androgen Excess
Worse with hyperinsulinemia
Hirsutism: 80% PCOS
Acne: 20% PCOS
Androgenic alopecia: 10% PCOS
PCOS

PCOS Etiology: Unifying theory?
PCOS

PCOS: Phenotypic & Genetic Variation
Susceptibility Genes
Modifier Genes
Environment
PCOS

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PCOS
Adapted from Luque-Ramirez et al, Clinica Chimica Acta, 2006.

PCOS
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PCOS: Diagnostic Criteria
PCOS
NIH/NICHD: USA, 1990
ESHRE/ASRM: Rotterdam, 2004
Androgen Excess‐PCOS Intl Society: 2006

PCOS Criteria
PCOS
NICHD/NIH Definition, 1990
Less inclusive
1 and 2 needs to be met:
Hyperandrogenism
clinical (hirsutism, acne, frontal balding)
biochemical (high serum androgen concentrations)
2. Menstrual irregularity
Chronic anovulation
Oligomenorrhea, > 35d
Rotterdam Definition, 2004
More inclusive
2 of 3 need to be met:
Hyperandrogenism
– Clinical or biochemical
Menstrual irregularity
3. **Polycystic ovaries **
(Key difference from NIH)
FOR BOTH: Exclude other causes (hyperprolactinemia, NC- congenital adrenal hyperplasia, thyroid disorder, etc.)

AE‐PCOS Society, 2006
PCOS
Hyperandrogenism**: Hirsutism and/or hyperandrogenemia
AND
Ovarian Dysfunction: Oligo‐anovulation and/or polycystic ovaries
Exclusion of other androgen excess or related disorders

Number 108, October 2009(Replaces Practice Bulletin Number 41, December 2002)

Polycystic Ovary Syndrome (PCOS)
EVALUATION
PCOS

Differential Diagnosis
PCOS
Premature ovarian failure
Idiopathic hirsutism
Other endocrinopathies: thyroid disorder, hyperprolactinemia, NC‐CAH, Cushing syndrome, etc.
Severe IR Syndromes (i.e., Syndrome X/Metabolic Syndrome)
Hypothalamic amenorrhea •
Neoplasm: rapid onset symptoms?
Ovarian (sertoli‐leydig, granulosa‐theca, hilus‐cell)
Adrenal
Pituitary/hypothalamic
Drugs (i.e., steroids)
HAIR‐AN syndrome
HyperAndrogenism,
Insulin Resistance,
Acanthosis Nigricans

PCOS: Menstrual Dysfunction
PCOS
25‐30% of women with oligo‐anovulation have PCOS
≥35 day intervals or <10 bleeds per year
2/3 of patients with PCOS have oligo‐anovulation
PCOS patients may describe “normal” menses, but further investigation reveals chronic anovulation in ~25%
Consequences:
Menstrual Dysfunction
Infertility
Endometrial hyperplasia/cancer

Polycystic ovaries ≠ PCO syndrome
Transvaginal sono is best
Incidence decreases with age
Sonogram Morphology:
>12 follicles/ovary @ 2–9 mm diameter
Volume: >10mL
– +/‐ “string of pearls”
Rule of 20%:
20% of women with PCO have PCOS
PCO absent in ~20% with PCOS
Present ~20% without PCOS
Hypothalamic amenorrhea
Adolescents
Hyperprolactinemia
PCOS

Assessing Hirsutism
Hirsutism vs virilization: rapidly developing virilization or certain virilizing symptoms (i.e., clitoromegaly, voice deepening) warrants further evaluation
Modified Ferrimen‐Gallwey
9 body parts, scored 0‐4 each
Score >6 hirsutism
PCOS
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PCOS: Physical Exam
PCOS
Blood pressure
Body mass index (kg/m2)
>25 overweight
>30 obese
Waist circumference > 35 inches, abnormal
Acanthosis nigricans: insulin resistant
Acne/alopecia: androgen excess
Galactorrhea: hyperprolactinemia
Thyroid
Stigmata of Cushings? (striae, moon facies, etc…)

PCOS: Basic Work‐up
PCOS
FSH & estradiol (E2) +/‐ LH:
premature ovarian failure (low E2; high FSH)
hypothalamic amenorrhea (low/normal E2; low FSH)
In [lean] PCOS, LH/FSH > 2
Free testosterone, normally <0.8% free
Prolactin & TSH
Mild elevations of prolactin more common in PCOS
Hypothyroidsim € hyperprolactinemia
NOTE: both conditions can produce PCO morphology on sonogram
Progesterone in luteal phase to confirm ovulation
>3 ng/mL
Can corroborate with sonogram monitoring of follicular development

Hyperandrogenemia in PCOS
A. Huang, et al., F&S, April 2010, N= 720 (NIH criteria)
Hyperandrogenemia present 75%
Hormone [Reference]
PCOS
[>88 ng/dL]
[>275 mcg/dL]
[0.66 ng/dL, >0.8%]

PCOS: Evaluation
PCOS
DHEA‐S
Mildly elevated in 30‐40% PCOS
adrenal tumors >700 mcg/dL € Pelvic/Adrenal contrast CT
Dexamethasone suppression test
17‐hydroxyprogesterone (17‐OHP):
Ashkenazi Jews, Latina, Mediterraneans, Inuits, Yugoslavians
Nonclassical CAH: AR, ~5% of presumed PCOS
Measure a.m. during follicular phase
Nonclassical CAH >4 ng/mL
Borderline: 2‐4 ng/mL € Cortrosyn stimulation test

PCOS: Optional Evaluation
PCOS
Total testosterone
Ovarian tumors >200ng/dL € get imaging
PCOS: upper limit of normal female, <80ng/dL
Use to calculate free testosterone
24‐hr urinary cortisol
Screen Cushing’s syndrome >50mcg/24h € need further testing

PCOS: Obesity
PCOS
NOT part of diagnostic criteria
Common in PCOS, affects between 50 to 80%
Waist‐to‐hip ratio >0.85 predicts insulin resistance better than BMI
Worsens phenotype

PCOS: Overweight?
PCOS
Screen impaired glucose tolerance or Diabetes
oral GTT: Fasting glucose € drink 75 gram glucola € repeat 2‐hour glucose; can also test insulin
Fasting: <100 normal; 100‐125 impaired; >126 DM‐II
2‐hour: <140 normal; 140‐199 impaired; >200 DM‐II
Fasting glucose/insulin < 4.5 (+/‐)
20% annual risk of developing glucose intolerance
Fasting lipid panel: elevated in nearly 70% of PCOS
HDL < 50 abnormal; TG > 150 abnormal

Metabolic Syndrome
15% of U.S. population
33% of PCOS!!
Adult Treatment Panel III (others exist):
Elevated blood pressure ≥ 130/85
Increased waist circumference ≥ 35 in
Elevated fasting glucose ≥ 100 mg/dL
Reduced high‐density lipoprotein cholesterol (HDL) ≤50 mg/dL
Elevated triglycerides ≥ 150 mg/dL

Polycystic Ovary Syndrome (PCOS)
TREATMENT: GOAL SPECIFIC
PCOS

PCOS: Goal Specific Therapy
PCOS
Screen and manage comorbidities
Hirsutism/acne/hair loss
Protect/monitor endometrium
Ultrasound +/‐ endometrial sampling
HRT/OCP (+/‐ insulin sensitizing agents) for endometrial protection and menstrual regulation
Incidentally may reduce hyperandrogenism (hirsutism, acne, etc.)
Fertility

PCOS: Co‐morbidities!
PCOS
Insulin resistance, ~30%
Type‐II DM, ~10% (3‐5x)
Gestational diabetes (2.5x)
Endometrial hyperplasia/ atypia/cancer
Metabolic syndrome/syndrome X
Sleep apnea/disordered breathing (Ehrmann, 2006)
related to IR NOT weight/BMI or androgens (30‐40x)
Depression
Sexual dysfunction

PCOS: Probable Links
PCOS
Coronary artery disease
Dyslipidemia
Hypertension
Ovarian cancer (?)
Miscarriage (?)
Pregnancy induced hypertension/PIH (?)

Prevention of CVD and DM
PCOS
Lifestyle: weightloss and exercise!!
Metformin 1500‐2000 mg daily if documented impaired glucose tolerance or metabolic syndrome, otherwise limited evidence for use.
Statins: beneficial in long‐term for prevention, but must avoid pregnancy, since category X

PCOS: Endometrial CA
PCOS
56 obese PCOS women (Cheung,2001)
36% hyperplasia € 2% cancer without tx
9% atypia € 23% cancer without tx
Women >50 yrs with endometrial cancer, PCOS present in 62.5%

Summary: Sequelae of biochemical aberrations
PCOS

Treatment of Hirsutism
PCOS
Multi‐step approach is most‐effective:
Hair removal: wax, laser, eflornithine, etc.
OCPs for at least 3 months, (>18 months is best)
Metformin (+/‐)
Continuous progestin therapy
GnRH agonist (lupron): <6m use; many side‐effects
Anti‐androgens (USE with contraceptive!):
Spironolactone (100‐200mg/d): binds DHT intracellular receptor; in‐utero risk: incomplete virilization of male fetus
Finasteride (2.5mg q 3 d to 5mg/d): inhibits 5‐alpha‐ reductase (blocks T € DHT); in‐utero risk: male fetus hypospadias
Steroids: many SE, reduces androgens, ok short‐term

Treating PCOS anovulatory infertility
PCOS

PCOS: Weight Loss
PCOS
Frequency of obesity in women with anovulation and PCO: 30%‐75% ‐‐ most before puberty
5‐10% weight loss restores ovulation >55% < 6months (Kiddy, 1992)
Weight‐loss program for anovulatory obese women:
Lost 6.3 kg (13.9 lbs) on average
Decreased fasting insulin and testosterone levels
Increased SHBG concentrations
92% resumed ovulation (12/13)
85% became pregnant (11/13)

PCOS and Infertility: Metformin?
PCOS
Metformin (biguanide ): improves insulin resistance
reduce hepatic glucose production & intestinal absorption
Increase peripheral glucose uptake
increase SHBG € reduce androgen levels
Major side effect of metformin is GI (n/v/d)
Metformin 500mg qD for 1 week € 2000mg daily
Can use extend release dosing, qd @ dinner
Risks/Contraindications
Renally excreted (Cr<1.4)
Hepatotoxic ‐‐ avoid with elevated transaminase
Lactic acidosis (RARE!)
Stop 1 day before IV contrast dye study or surgery

PCOS and Infertility: Metformin?
Legro et al., NEJM 2007
MC‐RCT, 6 months
No screening for IR
Medications started concomitantly
No difference in SAB rates
PCOS
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PCOS Fertility Options: Ovulation Induction (OI)/Superovulation (SO)
Clomiphene Citrate: non‐steroidal weak estrogen related to diethystilbestrol, SERM
Clomid:
start cycle‐day 2, 3, 4, or 5
take for 5 days (less common protocols exist)
Dose 50mg/day to 200 mg/day (take pills once per day, not bid/tid/etc…
Ovulate ~80% € 60% pregnant < 6m for OI patients
Consider letrozole/femara: aromatase inhibitor, may have less negative impact on endometrial thickness
PCOS

PCOS Fertility Options: OI/SO (2)
Gonadotropins: HMG, FSH
60% live‐birth 12‐18 mo
Need careful monitoring (follicle scans, estradiol levels)
OHSS (~1‐2%)
Multiple gestation risk (~20‐30%)
Risk of multiples may be hard to modify
Combine with clomid to reduce risks and costs of treatment (i.e., start with clomid cycle day 3‐7, then add gonadotropins)
PCOS

PCOS Fertility Options: ART
PCOS
Assisted Reproductive Technologies (ie, IVF/ICSI)
PROS
Highly successful in PCOS: >60% OPR/cycle in <35 yo
Efficient: Usually have supernumery embryos that can be cryopreserved for future use (~70%)
Can modify risk of multiples (i.e., elective single embryo transfer)
CONS
[Relatively] expensive (per cycle) € though increasing evidence that this is more cost‐effective per live born…
Risk hyperstimulation

PCOS Fertility Options: Surgery
PCOS
Laparoscopic wedge resection or ovarian drilling
PROS
May avoid fertility treatment risks (i.e., multiples, OHSS)
May identify and treat other comorbidities (i.e., endometriosis, pain, adhesions)
Intraoperative findings may alter treatment decisions CONS
Relatively invasive
Doesn’t universally restore ovulation ~50:50
Postoperative adhesions
Iatrogenic compromise to ovarian function/reserve
Limited data support its efficacy
Gonadotropins likely to be successful (70% vs. 60%)

PCOS: Pharmacotherapy summary
PCOS

PCOS: Conclusions (1)
PCOS
Multifaceted condition with varying presentation
No clearly accepted basis for diagnosis
Significantly associated health consequences
Genetic and pre‐natal implications
Metabolic disorder with risk of long term health complications: DM, cardiovascular, obesity, etc.
Reproductive repercussions: Endometrial hyperplasia € cancer; menstrual irregularities; infertility