1- Polycystic Ovarian Syndrome

(Stein Leventhal Syndrome -1935??)

Definition :
 A syndrome ccc by  ov. Dysfunction & loss of
hormonal cyclicity presented by  infertility, obesity,
hirsutism, anovulation of  unknown etiology that
affects  5-10% of females (20 – 30 yrs).
 It is equaly affects all races and more prevalent in
south Asian with more severe symptoms.
 Ethnic variation:
o relatively mild phenotypes in Caucasians.
o higher BMI in Caucasians, especially North America
and Australia.
o lower BMI and milder hirsutism in East Asians.
o higher BMI and metabolic features in Africans.
o more severe hirsutism in Middle Eastern, Hispanic and
Mediterranean women.
o increased central adiposity, insulin resistance, diabetes,
metabolic risks and acanthosis nigricans in South East
Asians and Indigenous Australians.
 It is the commonest cause of DUB , infertility and hirsutism.
Ovarian Hyperthecosis :
 Often considered a more severe form of PCOS, ovarian hyperthecosis is a rare
condition characterized by nests of luteinized theca cells distributed throughout the
ovarian stroma. Affected women exhibit severe hyperandrogenism and may
occasionally display frank virilization signs such as clitoromegaly, temporal balding,
and deepening of the voice (Culiner, 1949). In addition, a much greater degree of
insulin resistance and acanthosis nigricans is typically is found (Nagamani, 1986).
HAIRAN Syndrome:
 The hyperandrogenic-insulin resistant-acanthosis nigricans (HAIRAN) syndrome is
uncommon and consists of marked hyperandrogenism, severe insulin resistance,
and acanthosis nigricans (Barbieri, 1994). The etiology of this disorder is unclear, and
HAIRAN syndrome may represent either a variant of PCOS or a distinct genetic
syndrome.
 Both ovarian hyperthecosis and HAIRAN are exaggerated phenotypes of PCOS, and
their treatment mirrors that for PCOS
Pathophysiology :
 Etiology is unknown . however , a genetic basis that is both multifactorial
and polygenic is suspected as there is increased prevelance in affected
patients and their sisters & mothers. Some suggested X linked dominant and
other suggested autosomal dominant expression.dysregulation of CYPIIa
gene of the theca cell has been suggested ( these gene encodes the
cholesterol side chain cleavage enzyme that perform the rate limiting step in
steroids bio-synsthesis.
 Others suggest upregulation of enzymes in androgen biosynthesis.
 Also insulin receptor gene on chromosome 19 p 13.2 may be involved.
 So recently it is suggested that the etiology of PCOs is attributed to obesity
with insulin resistence which leads to alteration in ovarian peptides
responsible for enzymatic activity.
 A Vicious cycle, may be d.t. :
- Primary CNS error  hypothalamus, pituitary.
- Primary endocrinological (enzymatic) error  ovary ( aromatase
deficiency), adrenal( androgenic behavior), liver. Resulting in
hyperandrogenemia esp. testosterone.
 There is high LH :
Stimulates androgen formation by theca cells & ovarian stroma 
Part of this androgen is transformed locally (E2) & peripherally (E1) The
end result is increased both  androgens & estrogens.Also androgen
excess explained by genetic deficiency of aromatase enzyme .
 This will inhibit FSH release :
Thus follicular development is arrested at various stages. Also, local
androgens lead to atresia of follicles & thick capsule  multiple cysts
in the ovary but with no CL  anovulation & infertility.
 These follicles will further increase E :
 +ve feedback on LH () & -ve feedback on FSH ()  vicious cycle
 Stimulation of endometrium leading to :
- Short periods of amenorrhea followed by PPI bleeding.
- Proliferation of endomet  hyperplasia  carcinoma.
Associating insulin resistance is found in 40% of PCO
  local ovarian ILGF stimulation of androgen synthesis
 Androgens :
1…   insulin resistance furthermore.
2…   SHBG   free E & An furthermore.
3…  central obesity   SHBG furthermore.
4…..  granulosa cell apoptosis and anovulation.
NB:
 increased testosterone leads to thickening of tunica
albugenia and atresia of ovarian follicles.
 The exact mechanism of insulin resistence is not fully
understood , in obese patient s it may be a
consequence of alteration in some adipokines (resistin
which is involved in insulin resistence). In non obese
patient the mechanism is not well known but it is
possible that some form of adipose cell dysfunction still
present.
 Serum leptin( produced by fate cells) are elevated in
some PCO patients. Leptin production is regulated by
 insulin , so , it could be linked to metabolic and
neuroendocrine derrangment characteristic of PCO.
 Role of AMH:
 AMH or " mullerian inhibitory factor" is diametric protein fromed
of 2 peptide chains related to TGF-β family , that sectreted by
preantral and small antral follicles and correlated with the
number of remaining follicles in ovary.
 It is Not surprisingly, AMH levels are two- to three folds higher in
women with PCOS compared with nonaffected age-matched
controls.
 The increase of AMH in PCO is not only due to increased number
of small follicles but also increased secretion of AMH per
follicle→
 AMH lower the sensitivity of follicles to FSH→ deranged
follicular selection.
 AMH inhibits aromatase activity , hence , follicles from PCO
womrn donot produce large amount of E2 but produce high
androgens→ +ve feedback mechanism between AMH and
testosterone levels.
Pathology :
 Uterus …… unopposed E  symmetrically enlarged.
 adenomyosis ± end. Hyperplasia.
Endometrium may be atrophic due to excess androgen!!!!.
 Ovaries …… (polycystic, sclerocystic) :
- Size  enlarged 2 – 4 times.
- Tunica albuginea  thick, ivory
white, smooth (no stigma of
ovulation).
- Cysts  multiple, small(2-9mm),
subcapsular filled with clear fluid
(rich in E+A).
- Stroma  hyperplasia of theca
& stroma cells (stromal hyperthecosis)due to high LH stimulation.

Diagnosis by :
Old criteria - two schools:
o American (NIH/NICHHD 1991)Hyperandrogenism
o European - mainly USS
Recently Diagnosed by Rotterdam criteria (2003):
1. Clinical or biochemical Oligo-ovulation and/ or anovulation.
2. Clinical picture and / or biochemical signs of hyperandrogenism.
3. Ultrasonic criteria suggestive of PCO
  However, because other etiologies, such as congenital adrenal hyperplasia
androgen-secreting tumors, and hyperprolactinemia, may also lead to
oligoovulation and/or androgen excess, these must be excluded. Thus, PCOS
is at present a diagnosis of exclusion.

It is important to note that this US findings donot apply in women taking OCP
, also if dominant follicle is found then the scan need to be repeated in the
next cycle.
Androgen Excess Society(AES) criteria for diagnosis of PCO
(2006):
1. Documented hyperandrogenism(hirsutism and /or
hyperandrogenemia)
2. Ovarian dysfunction( oligo-anovulation and / or anovulation and / or
polycystic ovary).
3. Exclusion of other androgen excess or related disorders (2009)
NIH criteria for diagnosis of PCO ( 1990): applied for adolescents
1. Chronic anovulation (> 2 years)or menstrual dysfunction.
2. Clinical and /or biochemical signs of hyperandrogenism( Testosterone
level).

DIAGNOSIS Steps (acc. To ESHRE , 2018)

 Step 1: Irregular cycles + clinical hyperandrogenism(exclude other causes)
 Step 2: If no clinical hyperandrogenism Test for biochemical
hyperandrogenism (exclude other causes).
 Step 3 : If ONLY irregular cycles OR hyperandrogenism→
o Adolescents →ultrasound is not indicated = consider at risk of PCOS
and reassess later.
o Adults → request ultrasound for PCOM, if positive(exclude other
causes)
 Exclusion of other causes requires
1. TSH, Prolactin, FSH
2. if clinical status indicates other causes need to be excluded →CAH,
Cushings, adrenal tumours

1. Suggestive clinical picture :

 The major features of PCOS include menstrual dysfunction,
anovulation, and signs of hyperandrogenism.
o Symptoms … a variable scope of C/P (SOHA) …
1)Anovulation and irregular menstruation (periods of
amen / oligohypom  PP bleeding)  ,but 20% have
normal menses.
 Oligomenorrhea = menstrual bleeding that occurs at
intervals of 35 days to 6 months, with < 9 menstrual
periods per year)
 Irregular menstrual cycles (ESHRE , 2018)
 - Normal in the first year post menarche =
pubertal transition.
- > 1 to < 3 years post menarche: < 21 or > 45
days.
- > 3 years post menarche to perimenopause:<
21 or > 35 days or < 8 cycles per year.
- > 1 year post menarche > 90 days for any one
cycle.
- Primary amenorrhea by age 15 or > 3 years
post thelarche (breast development).
 With irregular cycles →PCOS should be
considered and assessed according to the
guidelines.
 Ovulatory dysfunction→ can still occur with
regular cycles.
 If anovulation suspected →test progesterone
levels.
2)Infertility ± habitual abortion (probably d.t. the high LH).
3)Hirsutism & acne (clinical hyperandrogenism) -70%, +
acanthosis nigricans(insulin resistence).
 Adults: acne, alopecia and hirsutism.
 Adolescents: severe acne and hirsutism.
 Associated negative psychosocial impact→
Perception of unwanted face and body hair and/or
alopecia are important, regardless of apparent clinical
severity.
 Hirsutism prevalence is same across ethnicities and
self-treatment is Common and can limit clinical
assessment.
 the most common areas affected with excess
hair growth in women with PCOS include
the upper lip, chin, sideburns, chest, and
linea alba of the lower abdomen.
 Premature adrenarche is a common
occurrence and, in some cases, may
represent a precursor to PCOS. Hirsutism
and obesity may be present in
premenarchal adolescent girls with
PCOS.
 The modified Ferriman-Gallwey (mFG) :
1. score grades 9 body areas from 0 (no
hair) to 4 (frankly virile), including the
upper lip, chin, chest, upper abdomen,
lower abdomen, thighs, back, arm, and
buttocks. A total score of 8 or more is
considered abnormal for an adult white
woman; a score of 36 is the most severe.
 2. A cut-off score of ≥ 4-6 indicates
hirsutism, depending on ethnicity.
3. Only terminal hairs relevant in
pathological hirsutism (untreated > 5 mm
long, variable shape and pigmented).
 Assessing alopecia.→The Ludwig visual score.

 Biochemical hyperandrogenism is most useful

when clinical hyperandrogenism is unclear . Using
High quality assays needed for most accurate
assessment and Interpretation of androgen levels
should be guided by the reference ranges of the
laboratory used.
 Use
i. calculated free testosterone
ii. free androgen index or
iii. calculated bioavailable
testosterone in diagnosis.
 Androstenedione and
dehydroepiandrosterone sulfate (DHEAS)
have limited role in PCOS diagnosis.
 Direct free testosterone assays not preferred.
 On hormonal contraception Reliable
assessment of biochemical
hyperandrogenism not possible , so Consider
withdrawal for ≥ 3 months before testing,
advising non-hormonal contraception during
this time.
 Where levels are well above laboratory
reference ranges ,
1. Other causes should be considered.
2. History of symptom onset and
progression is critical in assessing for
neoplasia
3. Some androgen-secreting neoplasms
may only induce mild to moderate
increases in biochemical
hyperandrogenism.
4)Obesity -50%, (obesity = BMI > 27 kg/m2). Tends to be
central ( abdominal characterized by a waist circumference
 greater than 35 inches (>88 cm)) with increased BMI and
waist-hip ratio(determine fat distribution) > 0.75= abnormal
o Signs :
 General: obesity , DM, HTN , anemia from bleeding.
 Symmetrically enlarged uterus.
 Bilateral enlarged ovaries.

2. Ultrasonic criteria suggestive of PCO ( Ultrasound and polycystic ovarian

morphology (PCOM)):
- Ultrasound should not be used < 8 years after menarche {high
incidence of multi-follicular ovaries in this life stage}(ESHRE ,
2018)
 Adams Criteria
 Necklace appearance ( 10 subcapsular cystic
follicles)
 Each cyst is 6 – 10 mm in diameter  microcysts

 The whole ovarian volume is increased > 10 cm3

 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 (0.5 × length
3
×width×yhickness >10 cm ) or both & only one ovary is sufficient
for diagnosis.
 Doppler US : shows increased blood flow to the stroma.
NB:
 a polycystic ovary should not be confused with a multicystic
ovary, which is normal size, contains six or more
follicles without peripheral displacement, and lacks
an increase in central stromal volume.
 a polycystic appearance of the ovaries can often be found in
other conditions of androgen excess, such as
congenital adrenal hyperplasia, 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.
… These findings are Normal in 25% (polycystic like ovaries) As it may
occurin any case of prolonged anovulation + hyper 'E'
…. 15 % of patiens on OCP show U/S criteria of PCO.

 The transvaginal ultrasound approach Preferred if sexually

active and acceptable to the individual being
assessed.
 with a frequency bandwidth that includes 8MHz, the threshold
for PCOM should be
1. follicle number per ovary of ≥ 20 and/or
2. an ovarian volume ≥ 10ml on either ovary
3. ensuring no corpora lutea, cysts or dominant
follicles are present.
 If using older technology threshold for PCOM could be an
ovarian volume ≥ 10ml on either ovary.
 In patients with irregular menstrual cycles and
hyperandrogenism an ovarian ultrasound is not
necessary for PCOS diagnosis; however ultrasound
will identify the complete PCOS phenotype.
 Transabdominal ultrasound should primarily report ovarian
volume with a threshold of ≥ 10ml,{difficulty of
reliably assessing follicle number with this approach}
3. By laparoscopy  large ovary with smooth, white ivory capsule
4. Specific hormonal changes :
 Exclude all other disorders that can result in menstrual
irregularity and hyperandrogenism, including adrenal or
ovarian tumors, thyroid dysfunction, congenital adrenal
hyperplasia, hyperprolactinemia, acromegaly, and Cushing
syndrome. [
  LH( 40%),  FSH … LH/FSH ratio  2.5  ( in 60 % only )
 NB: LH levels are affected by sample timing within a
menstrual cycle, use of oral contraceptive pills, and
BMI.
  Androgens (testosterone, androstenedione, DHEAS) .
 Low SHBG( it is decreased by androgen , corticoids , insulin,
progesterone & GH).
  Estrogens (E1 mainly).
  Prolactin (< 30 ng/ml).
 Serum TSH as thyroid disease may lead to clinical picture similar
to PCO Syndrome ( anovulation).
 Serum cortisol : as cushing $ leads to C/P as PCO e.g. menstrual
irregularity , acne, obesity , dyslipidemia & glucose intolerance.
  Fasting Insulin ( normally :10-20U/ml)→ hyperinsulinemia
(fasting glucose / insulin ratio < 4.5) and other insulin resistance
tests e.g. ↑HOMA-IR? And ↓QUICKI?
  Serum 17-OH progesterone to exclude non classical CAH as it
may cause hyperandrogenemia.
 Late-onset congenital adrenal hyperplasia due to 21-
hydroxylase deficiency can be ruled out by measuring
serum 17-hydroxyprogesterone levels after a cosyntropin
stimulation test. A 17-hydroxyprogesterone level of less
than 1000 ng/dL—measured 60 minutes after cosyntropin
stimulation—rules out late-onset congenital adrenal
hyperplasia.
 Lipid profile for dyslipidemia.
  Progesterone (mid-luteal) … anovulation  .
 some view AMH as a potentially useful diagnostic marker for
PCOS.
 should not yet be used as an alternative for the
detection of PCOM or to diagnose PCOS.
 - 1 level should be
checked to rule out acromegaly. Serum IGF-1 is a sensitive and
specific marker of growth hormone (GH) excess. Normal levels
rule out GH excess.
 The Royal College of Obstetricians and Gynaecologists (RCOG)
recommends the following baseline screening tests for women
with suspected polycystic ovarian syndrome (PCOS): thyroid
function tests, serum prolactin levels, and a free androgen index
(defined as total testosterone divided by sex hormone binding
globulin [SHBG] × 100, to give a calculated free testosterone
level).
1. RISK ASSESSMENT
1. Cardiovascular disease risk and weight management
 All with PCOS should be offered regular monitoring for
weight change and excess weight , Monitoring could be
at each visit or at a minimum 6-12 monthly:
1. Weight, Height
2. ideally waist circumference
3. BMI (should follow WHO guidelines)
 All with PCOS should be assessed for individual CVD
risk factors and global CVD risk If screening reveals
CVD risk factors including
1. obesity
2. cigarette smoking
3. dyslipidemia,
4. hypertension
5. impaired glucose tolerance and
6. Lack of physical activity, women with PCOS
should be considered at increased risk of CVD.
 Overweight and obese women with PCOS, regardless of
age should have a fasting lipid profile
1. total cholesterol
2. low density lipoprotein cholesterol
 3. high density lipoprotein cholesterol and
4. triglyceride level at diagnosis
 Thereafter, measurement should be guided by the
results and global CVD risk.
 All women with PCOS should have blood pressure
measured annually.
2. Gestational diabetes, impaired glucose tolerance and type 2
diabetes
 Regardless of age, gestational diabetes, impaired
glucose tolerance and type 2 diabetes are increased in
PCOS, with risk independent of, yet exacerbated by
obesity
1. 5 fold in Asia
2. 4 fold in the Americas
3. 3 fold in Europe.
 in all with PCOS Glycaemic status should be assessed
at baseline thereafter, every one to three years, based on
presence of other diabetes risk factors.
 In high risk women with PCOS , OGTT is
recommended. Otherwise fasting glucose or HbA1c
should be performed Including:
1. BMI > 25kg/m2 or in Asians > 23kg/m2
2. history of abnormal glucose tolerance or
3. family history of diabetes,
4. hypertension or
5. high risk ethnicity
 OGTT should be offered in all with PCOS :
1. when planning pregnancy or seeking fertility
treatment {increased hyperglycaemia and
comorbidities in pregnancy}.
2. If not performed preconception, an OGTT
should be offered at < 20 weeks gestation.
3. all women with PCOS should be offered the
test at 24-28 weeks gestation

3. Obstructive sleep apnea (OSA)

 Screening should only be considered to identify and
alleviate related symptoms:
1. snoring,
2. waking unrefreshed from sleep,
3. daytime sleepiness
4. the potential for fatigue to contribute to moo
disorders.
 If women with PCOS have OSA symptoms and a
positive screen(Berlin tool) should ideally be referred to
a specialist centre for further evaluation.
 4.Endometrial cancer :
 in women older than age 35 with abnormal bleeding and in
younger women with anovulatory bleeding refractory to
hormonal treatment.
 Two to six fold increased risk of endometrial cancer, often
presents before menopause however absolute risk remains
relatively low.
 a low threshold for investigation of endometrial cancer in PCOS,
with
1. transvaginal ultrasound and/or
2. Endometrial biopsy
 Recommended with :
1. persistent thickened endometrium and/or
2. risk factors (e.g. prolonged amenorrhea , abnormal
vaginal bleeding or excess weight).
 Routine ultrasound screening of endometrial thickness in PCOS is
not recommended.
 Optimal prevention for endometrial hyperplasia and endometrial
cancer is not known.
 A pragmatic approach for prevention could include
1. COCP or
2. progestin therapy in those with cycles longer than 90
days.
 NB:
1. for cushing syndrome diagnosis is by serum cortisol & 24 h urinary
collection for cortisol( normally < 90µg/dl & if > 300µg/dl then
diagnosis of cushing $)+ C/P ( moon face , abdominal stria , trunkal
obesity , proximal muscle weakness , easy bruising)
2. Dexamethasone suppression test is alternative to 24 h urinary
collection ( 1mg dexamethasone at 11 pm & measure serum cortisol
at 8 Am but with high false positive rate)

Differential diagnosis of PCOS:

1. Ovarian hyperthecosis
2. Congenital adrenal hyperplasia (late-onset)
3. Drugs (eg, danazol, androgenic progestins)
4. Hypothyroidism
5. Patients with menstrual disturbances and signs of hyperandrogenism
6. Idiopathic hirsutism
7. Familial hirsutism
8. Masculinizing tumors of the adrenal gland or ovary (rapid onset of signs of
virilization)
9. Cushing syndrome (low K+, striae, central obesity, high cortisol; high
androgens in adrenal carcinoma)
10. Hyperprolactinemia
 11. Exogenous anabolic steroid use
12. Stromal hyperthecosis (valproic acid)
Complications … Long term risks …
1. Hyperplastic endometrium & ↑risk of endometrial car.
2. DM.
3. CVD & HTN→HDL, LDL, cholesterol.
 Hyperinsulinemia →dyslipidemia and for elevated
levels of plasminogen activator inhibitor-1 (PAI-1)
→ are a risk factor for intravascular thrombosis.
4. During pregnancy :  incidence of DM . PIH , preterm
labour & abortion ( as high LH early meiosis and aged oocytes or
insulin resistance may be the cause). Hyperandrogenemia is suggested
to program the fetus to develop PCO at puberty!!!.
5. Obesity & metabolic syndrome(syndrome X).
6. Obstructive sleep apnea is more common in women with PCOS and is likely
related to central obesity and insulin resistance
7. Psychologic problems: such as anxiety, depression, low self-esteem,
reduced quality of life, and negative body image.
8. Increased risk of abortion( 30%) which may be treated by GnRH agonist
(luprone) to reduce this risk.
 Acanthosis Nigricans.
 This skin condition is characterized by thickened, gray-brown
velvety plaques seen in flexure areas such as the back of the neck,
the axillae, the crease beneath the breast, the waist, and the groin.
 It is a cutaneous marker of insulin resistance.
 Insulin resistance leads to hyperinsulinemia, which is believed to
stimulate keratinocyte and dermal fibroblast growth, producing the
characteristic skin changes
 More common in obese women with PCO than normal weight .
 Also seen with malignancy of GIT as adenocarcinoma of stomache
& pancrease.
 Acanthosis nigricans is staged according to the scoring
system below:
 Absent (0): Not detectable on close inspection
 Present (1): Clearly present on close visual inspection,
not visible to the casual observer, extent not
measurable
 Mild (2): Limited to the base of the skull, usually does
not extend to the lateral margins of the neck
 Moderate (3): Extends to the lateral margins of the
neck but not visible anteriorly
 Severe (4): Visible anteriorly
 Severe (5): Circumferential

 Metabolic Syndrome (syndrome X) and Cardiovascular Disease

  This syndrome is characterized by insulin resistance, obesity,
atherogenic dyslipidemia, and hypertension. The metabolic
syndrome is associated with an increased risk of cardiovascular
disease (CVD) and type 2 DM.
 Prevelance is 45 % in women with PCO.
 Insulin resistance in PCOS can be secondary to a postbinding
defect in insulin receptor signaling pathways, and elevated insulin
levels may have gonadotropin-augmenting effects on ovarian
function. Hyperinsulinemia may also result in suppression of
hepatic generation of sex hormone–binding globulin (SHBG), which
in turn may increase androgenicity.
Treatment … … According to C/O … …
1. Life style modification:
a. Weight loss    hyperinsulinemia & hyperandrogenism(SHBG
& LH) & spontaneous resumption of ovulation.
b. Well balanced hypocaloric diet & exercise.
c. Bariatric surgery is indicated in women with morbid obesity ( BMI >
40kg/m2) ( NICE guidelines).
- should be considered an experimental therapy .
- Pregnancy avoidance during periods of rapid weight loss and for
at least 12 months after bariatric surgery with appropriate
contraception
- Types:
1. Laparoscopic Adjustable Gastric Banding (LAGB)→ restrictive or
intragastric ballon.
2. Roux-en-Y gastric bypass (RYGB)→ restrictive + malabsorptive.
- Perinatalrisks
1. small for gestational age
2. premature delivery,
3. possibly increased infant mortality
- Potential benefits such as reduced incidence of
1. large for gestational age fetus and
2. gestational diabetes
- If pregnancy occurs, the following should be considered:
1. awareness and preventative management of pre-and
post-operative nutritional deficiencies
2. monitoring of fetal growth during pregnancy.
d. Weight loosing drugs : sibutramine ( centrally acting serotonin and
norepinephrine uptake inhibitor) and orilsate (lipase inhibitor) and the
selective cannabinoid type I receptor blocker (Rimonabant).
i. Anti-obesity agents should be considered an experimental
therapy for women with PCOS for the purpose of
improving fertility

e. Stop smoking as it may increase adrenal androgen production.

2. If the main complaint is hirsutism :
 COC (1st line)…… containing 3rd generation 'P' e.g. Marvelon / Gynera /
Cylest
 Diane …… 35 g EE + 2 mg cyproterone acetate( for 21 day and stop 7
days every month.
 Spironolactone ( androgen receptors antagonist) 50-100 mg twice
daily orally.
 Cimetidine.
 Elfornithine hydrochloride.: antimetabolites topical creamapplied
twice daily which is irreversible inhibitor of ornithine decarboxylase (
enzyme necessary for hair follicle cell division and function).
 Finasteride : 5mg daily.
 Mechanical : depilation and epilation ( waxing , electrolysis and laser).
 Acne : is treated with antibiotics , antiandrogens, finasteride and
retinoic acid ( vit A compound) .
3. If the main complaint is irregular uterine bleeding :
- Medical :
 COC (1st line) : 21 days  stop 7 days  repeat for 3-6 m or
recommended for 5 years. use COC with 3rd generation P and
avoid preparations containing desogestrel( ↑ risk of TE)
 Progesterone :
 Provera (MPA) 10 mg for 10 days each month or LNGIU
 Prevents also end. Hyperplasia d.t. unopposed 'E'.
-D & C :
 Therapeutic  if medical therapy failed.
 Diagnostic  to exclude endometrial hyperplasia &
malignancy.
-Hysterectomy :
 Atypical hyperplasia or Endometrial carcinoma.
 In old patient  with failed medical therapy and D & C.
4. If pregnancy is desired :
- Medical :
 Induction of ovulation by Clomid. If failed:
 Letrozole ( Femara) which is aromatase inhibitor→ 2.5mg
daily.
 1 line(ESHRE , 2018)
st

 It is free of side effects on endometrium and cervical

mucus.
 Less risk of multiple pregnancy when compared with
CC.
 Clomid alone or with metformine ±HCG or metformin
alone!!!.
 CC could be used in preference in women with
PCOS who are obese (BMI is ≥ 30 kg/m2).
 If metforminis used in obese(BMI ≥ 30kg/m2)
CC could be added to improve ovulation,
pregnancy and live birth rates.
 CC could be combined with metformin, rather
than persisting with CC alone, in women with
PCOS who are CC-resistant.
 Multiple pregnancyincreased with CC use and
therefore monitoring needs to be considered.
 AMH Is used now tp predect clomiphene
citrate poor responders ( value < 1.2 ng/ml) is
used as cut off level to predict clomiphene
citrate responders).

 Clomid + dexamethasone 0.5 mg at bed time( in patients with
high DHEAS).
 Tamoxifen : equally effective as clomid.
 Gonadotrophins ( HMG) +HCG :
 in cases with resistence to clomid or intolerable side
effects.
 Used as second line agents in women with PCOS who
have failed first line oral ovulation induction therapy.
 could be considered as first line treatment in the presence
of ultrasound monitoring after counseling on cost and
potential risk of multiple pregnancy.
 should be used in preference to CC combined with
metforminin CC-resistance PCOS,
 Gonadotrophinswith the addition of metformin could be
used rather than gonadotrophinsalone, in CC-resistance
PCOS
 Either gonadotrophinsor laparoscopic ovarian
surgerycould be used in, CC-resistance PCOS, following
counseling on benefits and risks of each therapy.
 low dose gonadotrophin protocols optimize
monofollicular development
 Associated with increased risk of multiple pregnancy and
OHSS ( due to altered of FSH threshold for follicular
development and increased sensitivity large size cohort
of small intral follicle to FSH) .
 Gonadotrophininduced ovulation should only be
triggered when there are fewer than 3 mature follicles
and should be cancelled if
 1. there are more than 2 mature follicles
2. the patient advised to avoid unprotected
intercourse
 GnRH agonist in pulsatile manner.used more in pateints
with hypogonadotrophic hypogonadism ( not
recommended).
 Dexamethasone act by reducing production of androgens by
adrenal glands.
 Tubal patency testing should be considered prior to ovulation
induction for women with PCOS where there is suspected
tubal infertility.
 Pregnancy should be excluded prior to ovulation induction.
 Unsuccessful, prolonged use of ovulation induction agents
should be avoided, due to poor success rates.

 Oral hypoglycemics :
 metformin (Glucophage or Glucophage XR) 500 mg daily
with lunch increase after 1 w to 500 with lunch and
dinner then after 1 w 1  3 for 6-12m   insulin
resistance   androgens  spontaneous preg. Causes
GIT upset and lactic acidosis in pt with renal impairment.
 Thiazolidenediones(pioglitazone or risoglitazone)
→decreases androgen but → fluid retension . category C
in pregnancy
 Somatostatin analogue (Octeriotide) shows to reduce insuline
level, improves pulsatile Gn pattern, reduce LH , androgens and
ILGF-1 , and increased spontaneous and stimulated ovulation.
Long acting somatostatine analogue release (octeriotide LAR)
IM /28 day is formulated to avoid the daily SC multiple inections.
 Myoinositol and D-chiro-inositol alone or combined with folic
acid or CC is a Safe and Alternative Approach in the Treatment
of Infertile PCOS Women→↓ insulin resistenc →↓insuline level
and other gormones( FSH/LH , androgen and prolactin)→
improves ovulation and pregnancy rate.
 Mechanism : deficiency of inositol in the
inositolphosphoglycans is responsible for insulin
resistance.
 Inositol (in any form) should currently be considered an
experimental therapy in women with PCOS, with the evidence
on efficacy too uncertain to advocate this therapy (ESHRE ,
2018)

- Surgical  if failed induction(clomiphene resistant) :
 Laparoscopic ovarian drilling : by electrocuatery or laser ( YAG ,
CO2 or KTP) and multiple biopsy.
 could be second line therapy for CC resistant PCOS,
 could potentially be offered as first line treatment if
laparoscopy is indicated for another reason.
 Risks should be explained to all women with PCOS
considering laparoscopic ovarian surgery.
 Mechanism is unknown. But may be that the thermal
damage →release of inflammatory introvarian cytokines
with a paracrine effect on androgen production and
normalization of pituitary LH.
 Patient with high LH are more likely to respond to LOD ,
while those with marked obesity , marked
hyperandrogenism and prolonged periods of infertility
are more likely to be resistant.
 4-8 punctures in each ovary for 2-4 seconds each using
40watt (rule of 4).
 Advantages  less adhesions :- ovulation rate is 70-80 %
and pregnancy rate is 40-60%.
 Diasadvantages: pelvic adhesions & destruction of
ovarian tissue POF , diminished ovarian & use of
general anesthesia.
 So it must be followed by measuring serum AMH which
decreased after effective drilling.
 A small French study also suggested that surgical
management via ovarian drilling with hydrolaparoscopy
may be beneficial in cases of PCOS that are resistant to
clomiphene citrate.
 Bilateral wedge resection : no more done
 Ovarian surgical trauma may correct the error &
stimulates normal function.
 Removal of 1 4 or 1 2 of the ovary.
  Disadvantage  more adhesions :- pregnancy rate 50%.
 2 types of wedge resection are known: classical wedge (
with base at surface ) and inverted wedge (with apex at
surface)
-ART  if failed all other measures : IUI or IVF & ET.
- IVF third line ±ICSI
- where other ovulation induction therapies have failed.
- IVF is effective when elective single embryo transfer is
used, multiple pregnancies can be minimised.
- Counselingprior to starting treatment,
- Urinary or recombinant follicle stimulation can be used
and there is insufficient evidence to recommend specific
FSH preparations.
- Exogenous recombinant LH should not be routinely
used in combination with FSH
- GnRHantagonist protocol is preferred over
GnRHagonist long protocol as it Reduces:
1. duration of stimulation
2. total gonadotrophindose
3. incidence of OHSS
- HCG should be used at the lowest doses to trigger final
oocytematuration to reduce the incidence of OHSS.
- Triggering final oocytematuration with a GnRHagonist
and freezing all suitable embryos could be considered
with
i. a GnRH antagonist protocol.
ii. at an increased risk of developing OHSS
or
iii. where fresh embryo transfer is not
planned.
- An elective freeze of all embryos should be considered.
- Adjunct metformin
a. could be used before and/or during follicle
stimulating hormone ovarian with a
gonadotrophinreleasing hormone agonist
protocol, to improve the clinical pregnancy rate
and reduce the risk of OHSS.
b. Benefits in a gonadotrophinreleasing hormone
antagonist protocol to reduce risk of OHSS
- In a gonadotrophinreleasing hormone agonist protocol
with adjunct metformintherapythe following could be
considered:
a. dose of between 1000to 2550mg daily
b. commencement at the start of
gonadotrophinreleasing hormone agonist
treatment
 c. cessation at the time of the pregnancy test or
menses (unless the metformintherapy is
otherwise indicated)
d. side-effects
- in vitro maturation (IVM)
a. the maturation in vitro of immature cumulus
oocytecomplexes collected from antralfollicles”
(encompassing both stimulated and
unstimulatedcycles, but without the use of a
human gonadotrophintrigger).
b. could be offered to achieve pregnancy and live
birth rates approaching those of standard IVF
±ICSI treatment
c. without the risk of OHSS for women with
PCOS, where an embryo is generated, then
vitrified and thawed and transferred in a
subsequent cycle.
-Oophorectomy is an option for women not needing to be pregnant
with severe signs and symptoms of
hyperandrogens!!!!!.

ACOG recommendation for PCO:

Level A recommendation:
 The recommended first line treatment for ovulation induction remains the antiestrogen
clomiphene citrate.
 elfornithine + laser treatment is superior in treatment of hirsutism than laser alone.
level B recommendation:
 Women with a diagnosis of PCO should be screened for type 2 diabetis and
impaired glucose tolerance with a FG level followed by a 2 h glucose level after a
75 –g glucose load.
 Women with PCO should be screened for cardiovascular risk by determination of
BMI , fasting lipid and lipoprotein levels, and metabolic syndrome risk factors.
 Reducation in body weight →improved pregnancy rate and ↓ hirsutism , as well
as improvement in glucose tolerance and lipid level.
 If clomiphene failed to result in pregnancy , the recommended second line
intervension is either exogenous Gn or laparoscopic ovarian surgery.
 When using gonadotrophen to induce ovulation , low dose therapy is
recommended.
Level C recommendation::
 Combined low dose hormonal contraception are recommended as the primary
treatment of menstrual disorders.
 The effect of insulin sensitizing agents on early pregnancy are unknowen ,
metformin appear safe, but any additional effect on reducing pregnancy loss is
unknowen.
 All women with suspected diagnosis of PCOS should be screened with 17
hydroxyprogesterone value for nonclassical CAH.