Professional Documents
Culture Documents
Williams Gyn.
August 2013
Samuel Bezabih
PCOS
No universally accepted definition
Many expert dxtic criteria are avilable
Hyperandrogenism/Hyperandrogenimia
Oligo/Anovoulation(oligomenorrhoea/ Amenorhoea
III.
PCOS
The most common endocrine disorder of
reproductive-aged women
Incidence~ 4 to 12%
Etiology
the underlying cause of PCOS is unknown.
However, a genetic basis that is both
multifactorial and polygenic is suspected, as
there is a well-documented aggregation of the
syndrome within families
Etiology of PCOS
Candidate genes in PCOS:
Steroid biosynthesis and action
(CYP17, CYP11A, AR-androgen receptor, SHBG,
CYP21)
Gonadotrophic action and regulation
(Follistatin, LH -subunit, FSH -subunit, FSH
receptor)
Insulin secretion and metabolism
(Insulin receptor, IRS1, IRS2, PPARG, IGF2)
Cardiovascular disease (PAI-1, IL6, Adiponectin)
Irregular menses
Hirsutism/acne/androgenic alopecia
Infertility
Obesity
Metabolic disturbances
Abnormal lipid levels/glucose intolerance
Long-term consequences
1. Diabetes mellitus
2. Cardiovascular disease
3. Endometrial cancer
Pathophysiology
Altered GnRH pusatility (?Hypothalamic vs 20)
more LH secretion than FSH
50% PCOS- elevated serum LH
60% LH:FSH > 2
Ovary
LH
Insuline, IGF
+
SHBG
free-Testost.
+
+
2%
95%
T-SHBG
normal
free-Testost.
20%
80%
T-SHBG
in PCOS
2Follicle
cell theory bild?
Theca
cells
Granulosa cells
Aromatization
Diffusion of
Testosterone
Excess
Testosterone
binds to SHBG
Estradiol
T-SHBG
Functionalhyperandrogenemia
Inhibition of
follicle growth
Low estradiol
with poor -ve
feed back
LH high
Pathophysiology
Elevated androgen level may result from
High LH and low FSH level (LH: FSH)
stimulation of Theca Cells by LH , androgen synthesis in
the face of low granulasa cell aromatase activity
Decreased androgen conversion to E increased
intrafollicular androgen ( and serum level too)
Adrenal secretion
Patophysiology
Effects of ed androgen level ( IF and serum)
ed intrafollicular androgen
follicular atresia
ed circulating androgens
Dyslipidemia, Acne, Hirsuitism , Alopecia
Suppression of SHBG synthesis (ed free androgens )
ed peripheral conversion of androstenidione to
Estrone (E2)??E1??
chronic unopposed exposure of endometrium to
Estrogen E. hyperplasia , Eca
Chronic ve feedback on pitutary and
hypothalamusAnovulation
Pathophysiology-IR
Positive correlation between insulin resistance (IR) and
hyperandrogenism
Women with PCOS display greater degrees of IR and
compensatory hyperinsulinemia than non affected
women
Icreased rate of IR in both lean and obese women with
PCOS, compared with weight matched unaffected
controls
-cell dysfunction that is independent of obesity reported
in PCOS
Insulin Resistance
IR hyperinsulinemia , Effects of insulin
Suppression of SHBG production of liver
Stimulation of Androgen production by theca cell
Stimulation of LH-secretion
Acanthosis nigricans
Contribution to follicular atresia
Dyslipidemia
The classic atherogenic lipoprotein profile seen in
PCOS is characterized by
Elevated LDL& TG
Depressed HDL levels ,
Elevated total cholesterol:HDL ratios
Ovarian Hyperthecosis
Ovarian Hyperthecosis
is a rare condition characterized by nests of
luteinized theca cells distributed throughout the
ovarian stroma with increased production of
testosterone
Often Hx of gradual onset of hirsutism and frank
virilization
Affected women exhibit severe hyperandrogenism,
and may occasionally display frank virilization signs
such as clitoromegaly, temporal balding, and
deepening of the voice
Metabolic Syndrome
MS is associated with an increased risk of CV
disease and type 2 DM
characterized by:Insulin Resistance,Atherogenic
dyslipedimia,Obesity Hypertension
Dxtic criteria (Adult Treatment Panel III)
BP (> 130/85)
Waist circumference > 35 inches
FBS > 100mg/dl
HDL < 50mg/dl,
TG > 150mg?dl
Menstrual Dysfunction
Range from amenorrhoea to oligomenorhoea and
menometroragia with anemia
Effect of unopposed estrogen unpredictable bleeding
Androgens counteract against E endometrial atrophy
and amenorrhoea
Menstrual Dysfunction
Menstrual abnormality in PCOS begins at
menarchae
difficult to differentiate from anovulatory cycles
common in postmenarchal girls (50%) due to H-P-O axis
immaturity
Girls with PCOS continue to have M irregularity in the
mid teenage years while the unaffected etstablish
regular ovulatory cycles
SS of Hyperandrogenism
Androgen excess symptoms and signs vary b/n
races/ ethnicities
SS HA Typical in PCOS are
Hirsutism
Acne
Androgenic Alopecia
SS of Hyperandrogenism
Hirsuitism
Terminal hair (Coarse, dark pigmented) in male
like pattern i.e. On androgen sensitive regions
upper lip, chin, chest, thighs, lower abdomen
Distinct from Hypertechosis- generalized increase
in lanugo hairs( soft, lightly pigmented) usually 20
to drugs, malignancy--
SS of Hyperandrogenism-Hirsuitism
5 alpha reductase converts testestorone to DHT in the
hair follicles
Sexual Hair androgen dependent( face, pubic,
chest,back, thigh, breast-----)
Vellus hair (short soft,downy, unpigmented) converted to
terminal hair (coarse, pigmented ) by the action of DHT( to
some extent Testosterone) in the hair follicles
Hirsuitism is a vellus to terminal hair transformation
Irreversible even after androgen withdrawal
SS of Hyperandrogenism-Hirsuitism
IGF 1 stimulate 5 alpha Reductase activity
Anovulatory hyperandrogenic women with IR and
Hyperinsulinemia have ed IGF1 activity
Intensified Hirsuit response
Extent of hirsuitism varies with race or ethnicity (
concentration of hair follicles)
Asians-low HF concentration/unit area less
likely to have overt hirsuitism
Hirsuitism
Ferriman-Gallwey scoring system of hirsuitism
SS of Hyperandrogenism-Acne vulgaris
Acne that is particularly persistent or of late onset
should suggest PCOS
Hyperandogenism overstimulation of androgen receptors in the
pilosebaceous unit increased sebum production that eventually
leads to inflammation and comedone formation
SS of Hyperandrogenism-Alopecia
Female androgenic alopecia is a less common finding in
women with PCOS.
Hair loss progresses slowly and is characterized either by
diffuse thinning at the crown with preservation of the
frontal hairline or by bitemporal recession .
Its pathogenesis involves an excess of 5-alpha-reductase
activity in the hair follicle leading to a rise in DHT levels.
In addition, there is an increased expression of androgen
receptors in these individuals .
Under the influence of androgens, terminal hairs that were not
previously dependent on androgens revert to a vellus form and
balding results
Acanthosis Nigricans
Thickened, gray-brown velvety plaques seen in areas of
flexure such as the back of the neck, the axillae, the crease
beneath the breast, the waist, and the groin .
May be found in individuals with or without PCOS
Thought to be a cutaneous marker of insulin resistance,
IR leads to hyperinsulinemia, which is believed to stimulate
keratinocyte and dermal fibroblast growth, producing the
characteristic skin changes .
Among women with PCOS, AN is more common in obese
women (50 %incidence) than in those with normal weight
(5 -10 %).
Less commonly, it is seen with genetic syndromes or
malignancy of the GI tract, such as adenocarcinoma of the
stomach or pancreas
Obesity
Compared with age-matched controls, women
with PCOS are more likely to be obese, as reflected
by an elevated BMI and Waist:Hip ratio
Pear shaped vs. Apple shaped .
This ratio reflects an android or central pattern of
obesity, which itself is an independent risk factor
for cardiovascular disease
However women with PCOS donot necessarily
present with obesity `
~ 20% of women with PCOS are not obese (ACOG 2009)
Anovulation
Unknown Precise mechanism
Indirect evidences attribute anovulation to the
Large number of antral follicle cohort and IR
resumption of fertility/regular menses after
wedge resection/ laparascopic ovarian drilling and
metformin treatment
Infertility
Infertility or subfertility is a frequent
complaint in women with PCOS
results from anovulatory cycles.
PCOS is the most common cause of infertility
secondary to anovulation 80 to 90 percent
of cases
nd
DIAGNOSIS
Diagnosis Of PCOS
PCOS is a diagnosis of exclusion
other disorders that have clinical appearance
similar to PCOS need to be routinely ruled out
DDX
PCOS DDx
Anovulation/Menstrual dysfunction
Hypo/hyperthyroidism -- or TSH levels
Hyperprolactinemia-- Prolactin level
Hypogonadotropic hypogonadism -- FSH, LH, E2
POF--FSH and LH ,E2
PCOS LH:FSH> 2
LH and FSH levels have little additive value to the diagnosis
of PCOS. Although classically LH levels measure at least
twofold higher than FSH levels, this is not found in all
women with PCOS. Specifically, one third of women with
PCOS have circulating LH levels in the normal range, a
finding more common in obese patients (Arroyo, 1997; Taylor, 1997).
Moreover, serum LH levels are affected by sample timing
within a menstrual cycle, use of oral contraceptive pills,
and body mass index
Hyperandrogenism
Late onset CAH
PCOS DDx
17ydroxyprogesteroneP(>200ng/dl)
PCOS
Testosterone- usually elevated
DHEAS- may be mildly elevated
LH:FSH ratio typically > 2
*women with an abrupt onset, typically within several months, or sudden worsening of virilizing signs should
prompt concern for a hormone-producing ovarian or adrenal tumor
Patient Evaluation
TSH
Prolactin
17OH progestrone (CAH)
Cushing S screening
Metabolic abnormalities
OGTT
Fasting lipid and lipoprotein level
US
Polycystic ovaries, Em
abnormalities
Optional tests
LH,FSH (cause of amenorrhea)
Fasting insulin level (young with
severe stigmata of IR, HA or on
Ovuation Induction)
24hr urine free cortisol/ low dose
DST for late onset PCO symptoms
and stigmata suggesting Cushing
Syndrome)
Sonography
Sonographic criteria for polycystic ovaries from the
2003 Rotterdam conference include > 12 small cysts (2
to 9 mm in diameter) or an increased ovarian volume
(>10 mL) or both
Only one ovary with these findings is sufficient to
define PCOS.
However, criteria do not apply to women taking
combination oral contraceptive pills
Sonography is particularly important for women with
PCOS seeking fertility and in women with signs of
virilization.
TVUS is superior to TABUS
TABUS-preferable for virgin adolescents
Sonography
studies using sonography have shown that at
least 23% of young women have ovaries that
exhibit PCO morphology, yet many of these
women have no other symptoms of PCOS .
In addition, a polycystic appearance of the ovaries
can often be found in other conditions of
androgen excess, such as CAH, Cushing syndrome,
and exogenous use of androgenic medications.
For this reason, PCO morphology found during
sonographic examination is not used solely to
make the diagnosis of PCOS.
IR and Dyslipidemia
a 2-hr GTT is frequently used to exclude
impaired glucose tolerance (IGT) and type 2
DM
a fasting lipid profile is used to evaluate any
signs of dyslipidemia.
Abnormal values
Total cholestrol, HDL < 50 mg/dl
TG > 150 mg/dl
LDL are alculated using Fridewald equation
PCOS TREATMENT
Laser drilling of ovary for surgical treatment of polycystic ovarian disease- Telinde
Treatment
The choice of treatment for each symptom of
PCOS depends on a woman's goals and the
severity of endocrine dysfunction
Observation
women with PCOS who have fairly regular cycle
intervals (8 to 12 menses/ year) and mild
hyperandrogenism may choose not to be treated.
In these women, however, periodic screening for
dyslipidemia and DM is warranted.
Treatment of PCOS-General
Weight Loss- (by obese women) life style/diet modification
Wt loss lowers circulating androgen levels and
improves reproductive and metabolic abnormalities
Improved pregnancy rate, hirsutism, glucose and lipid
profile
Even a modest amount of weight loss (5% of body
weight) can result in restoration of normal ovulatory
cycles in some women.
This improvement results from reductions in insulin
and androgen levels, the latter mediated through
increases in SHBG levels
Effect of wt loss in women with PCOS and normal wt is
unknown
Wt Loss
Phamacologic wt loss agents show improved
ovarian function
Orlistat- intestinal lipid absorption inhibitor
Sibutramine- anorexic agent
Insulin sensitizers
Biguanides and Thiazolidinediones
Lower androgen level
Improve ovulation rate
Improve glucose tolerance
Effects on body wt
Biguanides (Metformin) decrease body wt
TZ increase body wt
Insulin sensitizers:
Metformin (used off label in PCOS)
Low circulating insulin levels increased SHBG level
Decreased androgen levels
Regular cycles
Increased ovulation rate (Cochrane Review, Lord 2003)
Improves hirsutism
Improved results of CC- or FSH-stimulation
Lord 2003
Ovulation
NNT
Placebo
Metformin
Clomiphene
citrate (CC)
Metformin +
CC
26%
42%
4.4
Insulin sensitizers:
Metformin in pregnancy:
reduces LH and androgen concentration
enhances uterine vascularity (Jakubowicz et al, 2001)
reduces PAI-I and endothelin-I (Palomba et al., 2005; Orio et al.,
2005)
Insulin sensitizers
Note: off-label use for metformin in PCOS patients (pregnant and
non-pregnant)!!!
Cyclic Progestins
in patients who are not candidates for COCs ,
progesterone withdrawal is recommended every
1 to 3 months.
Examples of regimens used include:
MPA, 5- 10 mg PO/Day for 12 days, or
micronized progesterone, 200 mg po/evening for 12
days.
Treatment- Hirsuitism
Acne treatment
Infertility Treatment