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PCOS (POLYCYSTIC OVARY SYNDROME):
DEFINITION:
Classic symptoms:
- Hirsutism
- Irregular menstrual cycles
- Obesity
- Classical ovarian morphology.
Diagnostic criteria for PCOS (1990 NIH-conference):
- Menstrual irregularity (chronic anovulation)
- Evidence of hyperandrogenism, either clinical (hirsutism,
acne, male pattern balding), or biochemical ( serum
androgen level)
- Exclusion of other causes of hyperandrogenism
(hyperprolactinaemia , non-classical CAH, androgensecreting tumors).
NB:
- Abnormal ovarian morphology alone is insufficient to make a
diagnosis of PCOS (20-25% of regularly ovulating women,
90% idiopathic hirsutism, 89% CAH) .
- Polycystic ovary morphology is consistent with, but not
essential, for the diagnosis of PCOS.
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PATHOPHYSIOLOGY:
3 major hypotheses:
- LH hypothesis: Primary neuroendocrine defect leading to
exaggerated LH pulse frequency and amplitude resulting in
ovarian hyperandrogenism.
- Ovarian hypothesis: A primary defect of sex steroid
synthesis or metabolism results in exaggerated ovarian
(adrenal) androgen secretion and anovulation.
- Insulin hypothesis: A unique defect in insulin action leading
to hyperinsulinemia resulting in excess androgen secretion
(augmentation of LH stimulation of ovarian androgen
production) and anovulation.
Interrelationship between abnormalities:
- Multiple pathophysiologic defects described as a selfamplifying circle.
- Still impossible to determine primary etiologic factor.
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LH hypothesis (Neuroendocrine aspects of PCOS):
Observations:
 LH (baseline/post-GnRH stimulation), normal FSH,  LH/FSH
ratio (> 2.5) (75% of PCOS)
Rapid GnRH pulse frequency favouring acyclic LH release:
possible mechanisms ( sensitivity of GnRH secretion to
inhibition by ovarian steroids):
- Neurotransmitters: Dopamine and endorphins are
inhibitory to GnRH release.
- Estrogens:
o Early “estrone hypothesis”:  peripheral
aromatisation of androstenedione   estrone  
pituitary LH secretion.
o Current evidence does not support a role for
persistent elevations of estrone in enhancing GnRH
pulsatile secretion, although a role in reducing FSH
responses to GnRH has been established.
- Androgens:
o Although not conclusive, several studies suggest
that excess androgen exposure (prenatal/
prepubertal) may modify subsequent regulation of
hypothalamic GnRH release.
- Insulin:
o Although not conclusive, several studies suggest
that hyperinsulinemia could enhance GnRH
secretion or pituitary responses to GnRH or both.
o Supported by reduction in LH after metformin or
troglitazone.
- Estrogen-progesterone feedback:
o Anovulation and absence of luteinization  
progesterone levels   negative feedback
(hypothalamic/pituitary).
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Ovarian hypothesis (Defective steroid synthesis/ metabolism):
Figure 1: Steroid biosynthesis in adrenal cortex.
Figure 2: Two-cell model of ovarian steroidogenesis.
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Generalised dysregulation (ovarian and adrenal) of steroid
biosynthesis and metabolism.
- Dysregulation of 17-hydroxylase and 17,20-lyase
activities, both properties of P450c17 (rate-limiting
enzyme in androgen biosynthesis)   activity.
- Results in functional ovarian hyperandrogenism (70% of
PCOS) and/or adrenal hyperandrogenism (50% of
PCOS).
- P450c17 gene expression is normally dependent on the
concentration of the respective trophic hormones (LH in
the ovary, ACTH in the adrenal cortex).
- The steroidogenic response to trophic hormones is
modulated by a multitude of intrinsic (autocrine/paracrine)
/ extrinsic (eg insulin, IGFs) regulatory mechanisms –
more important in women.
- Functional ovarian hyperandrogenism:
o Characterised by:  17-OH progesterone secretion
in response to GnRH agonist/HCG stimulation and
failure of dexamethasone suppression of free
testosterone (in presence of normal adrenocortical
suppression).
o Ovarian hyperresponsiveness to LH - escape of
thecal cells from normal downregulation in response
to increasing LH (? Insulin excess)
o Intensified by LH excess.
- Functional adrenal hyperandrogenism:
o Characterised by: moderately increased secretion of
17-ketosteroid DHEA in response to ACTH
(glucocorticoid-suppressible).
o Possible role for insulin excess.
- Disturbed peripheral steroid metabolism:
o Accelerated cortisol turnover   ACTH secretion
  adrenocortical activity
 Dysregulation of 11-hydroxysteroid
dehydrogenase ( cortisol  cortisone, 
urinary excretion of cortisol metabolites, 
ratio of 11-keto/11-hydroxy metabolites).
 Enhanced activity of 5-reductase (in liver) (
hepatic cortisol metabolism,  total urinary
cortisol metabolites,  ratio of 5/5metabolites).
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o Enhanced activity of 5-reductase (in skin) results in
 DHT levels (active/more androgenic).
o Obesity contributes to androgen excess by
formation of estrogen and testosterone from inactive
precursors.
Figure 3: Some principal pathways for cortisol metabolism.
Figure 4: Model of factors causing functional
hyperandrogenism.
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Insulin hypothesis:
First report of association of hyperinsulinemia / insulin
resistance and PCOS in 1980.
Figure 5: Molecular mechanisms of insulin action.
Figure 6:Molecular mechanisms of insulin resistance in PCOS.
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Hypotheses explaining the association of insulin resistance and
PCOS:
Causal association:
- Do androgens cause insulin resistance?
o Androgens may produce mild insulin resistance (
less insulin-sensitive type IIb skeletal muscle fibres,
 muscle glycogen synthase).
o Modest hyperandrogenism of PCOS may contribute
to insulin resistance, but additional factors are
necessary to explain the insulin resistance because
suppressing androgen levels does not completely
restore normal insulin sensitivity.
- Does hyperinsuliemia cause hyperandrogenism?
o Hyperinsulinemia augments androgen production in
PCOS:
 Dysregulation of P450c17
 Decreased hepatic production of SHBG.
o Intrinsic abnormalities in steroidogenesis seem
necessary for this insulin action to be manifested (
insulin levels: no affect on circulating androgen
levels in normal women, ameliorates but does not
abolish hyperandrogenism in PCOS).
o Insulin has specific actions on steroidogenesis
acting through the insulin receptor. These actions
seem to be preserved when there is resistance to
insulin action on carbohydrate metabolism –
selective defects in signalling pathways regulating
carbohydrate metabolism.
Possible genetic association of PCOS and insulin
resistance:
- Serine phosphorylation of P450c17 increases its 17,20lyase activity.
- Insulin resistance in PCOS appears to be secondary to
serine phosphorylation of the insulin receptor.
- Protein kinase A has been shown to serine phosphorylate
both in vitro.
- It is postulated that one or several genetic defects may
cause both the insulin resistance and reproductive
abnormalities of PCOS.
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BIOCHEMICAL ABNORMALITIES/ LABORATORY
DIAGNOSIS:
Laboratory diagnosis of PCOS is one of exclusion.
HORMONE PROFILE:
In PCOS:
- Estrogen: N follicular levels (> 150 pmol/l) (mainly from
peripheral conversion)
- Progesterone: 
- LH: 
- FSH: disproportionally N/
- LH/FSH ratio > 2.5 (75% of PCOS) (* also CAH)
ANDROGENS:
 DHEAS: Adrenal origin
 Testosterone: Ovarian/adrenal origin
In PCOS:
- S-Total testosterone: modestly  (< 5.2 nmol/l)/ normal
(due to  SHBG).
- Free testosterone:  - higher diagnostic yield
- DHEAS: N/slightly .
Exclusion of androgen-producing tumors: Consider if:
- Total testosterone > 200 ng/dl (6.9 nmol/l)
- DHEAS > 700ug/dl (19 umol/l)
17-OH PROGESTERONE (follicular phase):
Exclusion of non-classical/late onset CAH:
- < 6 nmol/l: Excludes CAH
- > 30 nmol/l: Confirms CAH
- 6.9-45 nmol/l: ACTH stimulation test (follicular phase):
o CAH: 60 min > 30 nmol/l
o * PCOS:  basal and stimulated 17-OHP, but
normal incremental change (17-OHP 30-0).
URINE STEROID PROFILE (follicular phase):
Distinguish between CAH and PCOS:
PCOS:
-  total urinary cortisol metabolites
-  5/5-metabolites
CAH:
-  urinary cortisol metabolites
-  cortisol precursors eg pregnanetriol.
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PROLACTIN/TSH:
- Exclusion of prolactinoma (Prolactin > 200 ug/l).
- 35% of PCOS patients have slightly  prolactin (lactotroph
stimulation by chronic estrogen).
- Coexistence of prolactinoma + PCOS uncommon.
- Abnormal thyroid function (/) associated with menstrual
irregularities.
ASSOCIATED BIOCHEMICAL ABNORMALITIES:
HYPERINSULINEMIA / INSULIN RESISTANCE:
Important to diagnose for institution of preventive strategies (diet,
exercise, insulin-sensitizing agents):
- Mild form: slightly  fasting insulin
- Ratio of fasting glucose/insulin (G in mg/dl, Insulin in
mIU/l) < 4.5: sensitive/specific marker in obese PCOS
IGT / DM:
All PCOS (obese/non-obese) have  risk (3x) for IGT/DM.
Screening with OGTT:
- Obese women before pregnancy is attempted.
- All PCOS after 40 y of age.
ALTERED SERUM LIPID PROFILE AND IMPAIRED
FIBRINOLYSIS:
Lipid abnormalities:
-  Total Chol
-  LDL-Chol
-  TGS
-  HDL-Chol / Apo A-I (most characteristic)
Impaired fibrinolytic activity:
-  PAI-1
Screening with fasting lipogram:
- All PCOS at 35 y of age
- If normal: repeat every 3-5 years
Women with PCOS have an estimated 7x increased risk for MI.
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DIFFERENTIAL DIAGNOSIS:
Table 1: Differential diagnosis of hyperandrogenism and menstrual
irregularity.
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PCOS
PATHOPHYSIOLOGY:
Combination of
abnormal ovarian
steroidogenesis /  LH
/ hyperinsulinemia
CLINICAL:
Irregular menses
(anovulation)
Gradual onset of mild
hirsutism
Onset at/soon after
puberty
Obesity
BIOCHEMICAL:
 Test (< 5.2 nmol/l)
N/slight  DHEAS
 LH/FSH ratio (> 2.5)
N Estrogen
 Progesterone
Ovarian
hyperthecosis
Non-classical CAH
Cushing’s
syndrome
Androgenproducing
neoplasms
Abnormal proliferation of
luteineised theca cells,
hypersensitive to
gonadotropin stimulation
21-hydroxylase
deficiency (90%)
Cortisol overproduction
(ACTH-dependent/
independent)
Ovarian or adrenal
tumors
Enlarged firm ovaries
Severe hirsutism of
gradual onset
Virilisation(clitoromegaly)
Obesity
Acanthosis nigricans
Resistant to
contraceptive therapy
Regular menses
Mild -severe hirsutism
of early onset
Premature adrenarche
Virilisation
(clitoromegaly)
Short stature
Familial tendency
Hirsutism
Obesity
Menstrual irregularity
Moonlike facies
Buffalo hump
Hypertension
Abdominal striae
Osteoporosis/muscle
wasting
Severe hirsutism of
rapid onset (within
months)
Virilisation(clitoromegaly)
Male body habitus
Palpable
pelvic/abdominal mass
 Test / DHEAS
LH/FSH low N / 
Estrone 
Insulin resist  ( Ins)
 17-OH progesterone  DHEAS/
 DHEAS (>700ug/dl/
(> 45 nmol/l)
 DHEAS /
androstenedione
 Test
N/ LH/FSH ratio
19 umol/l)
 Testosterone (> 200
ng/dl/6.9 nmol/l)
May be associated with
 Progesterone/cortisol
androstenedione
 Test (> 5.2 nmol/l)
 U-Free cortisol
N/ ACTH
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PCOS
Ovarian
hyperthecosis
PELVIC ULTRASOUND:
Polycystic ovaries (8-10 Bilateral noncystic
peripheral <8mm
enlargement
follicles,  stroma)
(80-100%)
Endometrial hyperplasia
OTHER IMAGING STUDIES:
Non-classical CAH
Cushing’s
syndrome
Androgenproducing
neoplasms
Polycystic ovaries
(80%)
Normal ovaries
Suspected ovarian
tumor
Abdominal CT/MR for
suspected adrenal
tumor
Abdominal CT/MR if
suspected adrenal tumor
( DHEAS)
REFERENCES:
1. Taylor AE. Polycystic ovary syndrome. Endocrinology and Metabolism Clinics of North America 1998 Dec;
27(4): 877-902.
2. Logo RA, Carmina E. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 2000
June; 132(12): 989-993.