Dr Thenmozhi Needhirajan DGO, MRCOG
Fellowship (University college London)
Consultant Obstetrician and Gynaecologist
Kurinji Hospitals, Coimbatore
Karpagam Medical College, Coimbatore
Poole Hospitals NHS Trust, United Kingdom
My work in India
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CEMENDS (Centre for Menstrual disorders & Gynae
Endoscopy) – Ambulatory Gynaecology
Lifetime screening programme for cervical cancer
Computerised recall system, Periodical smears, Colposcopy
Vulvoscopy for vulval leisions
Cervical cancer Vaccination
Cryotherapy
CEMENDS – Ambulatory Gynaecology
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Non – Hysterectomy Options for Menstrual disorders
Office Hysteroscopy for menstrual disorders
Medical management of fibroid
LNG-IUS
Transcervical Resection of Endometrium (TCRE)
Transcervical Resection of Fibroid/ polyp (TCRF)
NOVASURE Endometrial Ablation
Hysteroscopic Uterine Septoplasty for uterine septum
Menopause and Hormone Replacement Therapy
History and Epidemiology
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1st described by Irving Stein and Michael Leventhal as a triad of
amenorrhea, obesity and hirsutism (1935)
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The most common endocrine disorder in women of reproductive
age ~ 2%-8% of women
Knochenhauer ES et al, Journal of Clinical Endocrinology & Metabolism, 1998.
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Current suggested prevalence
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Caucasian: 4.8%
 African American: 8.0%
 Hispanic or Latino: 13%
 5%-10% of women
Azziz R et al, Journal of Clinical Endocrinology & Metabolism, 2004.
Goodarzi MO et al, Fertility and Sterility, 2005.
Ehrmann DA, New England Journal of Medicine, 2005.
What is PCOS?
A chronic condition characterized by
anovulatory infertility,
hyperandrogenism , hyperinsulinaemia,
insulin resistance
with clinical manifestations of
oligomenorrhoea,hirsutism and acne
Definition
1990 NIH DEFINITION
1. OLIGOMENORRHEA
2. HYPERANDROGENEMIA
3. Absence of other disorders such as
NCAH, Hyperprolactinemia, thyroid
dysfunction.
Rotterdam Criteria (2003)
Two of the three:
– Menstrual irregularity due to anovulation or
oligo-ovulation
– Clinical signs (Acne, Balding, Hirsuitism) or
biochemical hyperandrogenism
– Polycystic ovaries on ultrasound
Pathogenesis
OVARIAN HYPOTHESIS:
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– Thecal ( ovarian interstitial tissue)
hypertrophy,
leading to hyperandrogenemia
– excessive activity of an enzyme called 17,20
lyase
CENTRAL HYPOTHESIS:
abnormal GnRH pulse generation from the
hypothalamus leading to abnormal, increased LH
pulse amplitude and frequency
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Clinical Features
 Remember it is a syndrome, not a disease!
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It’s the most common disorder of the
Endocrine system in women, 5-10%
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Frequently begins around time of puberty
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Strong genetic component, frequently a
family history of type 2 DM
Consensus Workshop
3rd PCOS consensus workshop- Netherlands
Oct 2010
• Adolescence
• Hirsutism & Acne
• Contraception
• Menstrual cycle abnormalities
• Quality of life and sexual health
• Pregnancy complications
• Cardiovascular & cancer risk
PCOS in Adolescence
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No overall agreement on diagnosis
• Acne is common in adolescence
• Hirsutism typically develop over years
• Irregular periods also common
• Hyperandrogenaemia –consistent marker
• 85% of the menstrual cycles are anovulatory in the
first year
• Increased BMI –major risk factor for persistent
anovulation
• Only 40% of adolescents with irregular periods
have polycystic ovaries on USS
Diagnosis in Adolescence
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All 3 elements of Rotterdam criteria should be
present
Conclusions
• Diagnostic criteria should differ from from those
used for older women of reproductive age
• Groups at risk (obese, hirsute, irregular
periods))should be identified but be cautious of
over diagnosing
• Individual manifestations should be treated
Adolescent PCOS –Lack of knowledge
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Absence of longitudinal studies
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Absence of specific diagnostic criteria
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Absence of normative values for a number of
biochemical markers
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Value of intervention
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Unclear if the severity of the symptoms predicts
the extent of the disorder in later life
Hirsutism/Acne/Alopecia
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Hirsutism-Good marker for hyperandrogenism
Present in 70% of women with PCOS
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Hyperandrogenaemia should be evaluated biochemically
in all women
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Acne and Alopecia not commonly associated with
hyperandrogenaemia
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If Hirsutism major concern –
reduction in androgen production
decrease the circulating free testosterone
limit androgen bioactivity to hair follicles
terminal hair turnover occurs slowly- atleast 6
months treatment is essential
Treatment of Hirsutism/Acne/Alopecia
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Focused on
Inhibition of ovarian steroid production
Decreased bioavailability – Increase SHBG levels (OCPs)
OCPs often combined with antiandrogens to block androgen action at
hairfollicles
Antiandrogens – Cyproterone, Spirinolactone, flutamide, finasteride
drospirenone
Antiandrogens should not be used without contraception
Metformin has little effect on hirsutism and acne
Physical approaches to remove hair- electrolysis,laser
Severe Acne-Isoretinoin is beneficial
Topical use of Eflornithine hydrochloride- hirsutism
No effective pharmacological treatment for alopecia
Hirsutism/Alopecia/Acne
Lack of evidence
Unclear Best medical therapy for hirsutism
 Unclear how long therapy should be
continued
 Unclear how best to evaluate hirsutism
clinically
 Measurement of serum androgens is
fraught with error
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Menstrual Irregularity
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Women with PCOS may ovulate spontaneousely
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How frequent- unknown
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Oligo/amenorrhoea-90% chance of being diagnosed with PCOS
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Amenorrheic women- most severe hyperandrogenism/higher antral
follicle counts
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Menstrual cycles become more regular towards menopause
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Irregular periods are associated with increased metabolic risk
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The greater the irregularity the more severe the PCOS phenotype
Treatment of Menstrual Irregularities
 Weight Loss
Oral Contraceptives
 Provera
 – 5-10mg for ten days every 4-8 weeks
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Treatment of Infertility
 Weight loss 5-10% of body weight , 56%
had return of ovulatory cycles
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Gonadotropin Therapy
injection of FSH to stimulate ovulation
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Clomiphene - clomid
first line drugs
triggers ovulation in 80%,
Metformin
Metformin
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Metformin & PCOS
JCEM 2000 – Italy (Moghetti et al)
N=23 PCOS (mean BMI 30)
Randomized - Metformin 500 tid or placebo x 6
months
Androstenedione, 17OHP, estradiol, SHBG,
lipids
OGTT, insulin sensitivity with glucose clamp
Metformin & PCOS
Metformin & PCOS - Conclusion
Women on metformin lost weight,
 50% regular menstrual pattern
(of those 79% ovulatory cycles)
 Reduction in plasma insulin
 Decrease in Androgen levels
 baseline predictors-responders:
higher BMI, higher insulin level, lower serum
androgens less severe menstrual abnormalities
oScientific paper (RCOG) 2008 : PCOS &
infertility, role of metformin – No clear role,should
be limited to IGT and type 2 DM. not a first line
option
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Metformin vs Diane 35
JCEM 2000 – Finland (Morin-Papunen et
al)
 N= 32 (BMI > 27)
 Metformin 500 bid x 3m --> 1000 bid x 6m
vs Diane 35
 Metformin- decrease WHR, insulin,
improved oxidative glucose utilization
fasting free fatty acid, and menstrual
regularity
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Metformin vs Diane 35
 Diane - decrease serum testosterone levels
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Diane - worsening of glucose tolerance and
decrease insulin sensitivity
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Metformin possibly superior to Diane specially if
fertility is a concern
Is it safe to use metformin in women
attempting to conceive?
Mouse embryos - doses of 500-2550 mg
no major malformation of offspring
 Used in type 2 diabetes during pregnancy S.Africa
 5.5 year follow-up published
 Mig study
 Seems safe
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Contraception
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No methods are contraindicated in PCOS
Obesity,insulin resistance- relative CI to COCPs
OCPs suppress LH production –decrease in ovarian
androgen production
Estrogenic component increases SHBG
Progestin in the pill –compete for 5alpha reductase
OCPs also reduces adrenal androgen production
Contraception
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Overall, the benefits of OCPs outweigh the risks in most
patients
In the absence of other risk factors no evidence that women
with PCOS are at increased risk of CVD
No evidence for differences in effectiveness and risk among
the various progestogens and when used in combination
with a 20 versus 30 micrograms of estrogens
OCPs do not negatively affect subsequent fertility
No definitive evidence that the type of OCP determines the
efficacy of hirsutism control (evidence C)
Contraception - Knowledge gaps
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Head-to Head blinded trials comparing
different OCP strategies are lacking
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Lack of longitudinal FU studies after a
course of OCPs
Quality of life (QOL)
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At risk of psychological and behavioural
disorders- reduced QOL
PCOSQ
Significant detrimental effect compared to
controls
Weight issues were most apt to affect QOL
Eating disorders/sexual /relational dysfunction
Pshycological screening to improve long term
prognosis
Quality of life (QOL)
Knowledge gaps
Unclear if this increased prevalence is due to the
disorder itself or its manifestations
(Obesity, irregular periods,hirsutism,infertility)
Pregnancy
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Subfertility
Obesity,metabolic, inflammatory, endocrine
abnormalities on ovulatory function,,oocyte quality
and endometrial receptivity
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Ovarian hyperandrogenism Hyperinsulinaemia –
premature granulosa cell luteinisation – distrupt
the intrafollicular environment- impairs cytoplasmic
and nuclear maturation of oocytes
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These features are not universal
Pregnancy
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Early pregnancy embryo may be exposed to androgens –
long term effects
Data on risk of miscarriage – conflicting
40-50% risk of GDM and associated macrosomia,
gestational hypertensive disorders, SFD babies
Preconception counselling
Miscarriage rates are not increased after natural
conception,independent of obesity
Miscarriage rate after induction of ovulation mirror those
found in other infertile patients
Pregnancy
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AN care should be closely monitored
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Pregnancy associated risks are more in hyperandrogenic
women
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Babies may have increased morbidity and mortality
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No evidence for improved live birth rates or decreased
pregnancy complications with the use of metformin either
before conception or during pregnancy (Level A)
Pregnancy - Knowledge gaps
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Should pregnancies of women with PCOS have
increased antenatal monitoring including earlier
screening for GDM, additional dopplers
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Long term outcome of children born from women
with PCOS
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Long term outcome for women with PCOS who
develop GDM and gestational HT compared with
women with PCOS who don’t conceive
Obesity
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Widespread variability in the prevalence of
overweight (BMI 25-30 ) and obese(>30)
More likely to have upper body fat distribution
Greater abdominal or visceral adiposity –IR
IR – could exacerbate the reproductive and
metabolic abnormalities
Lifestyle interventions – substantial reproductive
and metabolic benefits
Type 2 Diabetes (T2D)
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PCOS is a major risk factor for developing
IGT/T2D
Obesity is an exacerbating factor in the
development of IGT/T2D in PCOS
Screening for IGT and T2D should be performed
by 75 gm OGTT
No utility for measuring insulin In most cases
Diet and lifestyle are first choice in improving
fertility and prevention of T2D
Cardiovascular disease Risk (CVD)
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Risk assessment should be done periodically
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Life long metabolic dysfunction in women with PCOS
exaggerates CVD risk especially after menopause
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All markers of CVD risk are higher in PCOS women
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Endothelial dysfunction in PCOS is related to abdominal
obesity and IR
Cancer risk
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PCOS disrupts normal reproductive physiology
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Increased risk of the development of CA endometrium
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Moderate quality data to support 2.7 fold increased
risk for endometrial CA.
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Most are well differentiated with good prognosis
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Limited data suggests that PCOS women are not at
increased risk of Ca ovary/breast
Menopause
Age may improve many manifestations of
PCOS including normalizing ovarian size and
morphology, T levels and oligo-ovulation prior
to menopause
Combined oral contraceptives
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Majority contain ethinyl estradiol
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Mestranol and Eastradiol valerate are also
used.
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The dose varies from 20-40 micrograms
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Always choose a preparation with the lowest
estrogen and progestogen content which gives
good cycle control and minimal side effects
Combined oral contraceptives
Low strength preparations
Ethinylestradiol 20 micrograms
 Std strength preparations
-30-35 micrograms
Progestogens(3rd generation)
desogestrel, drospirenone and gestodene In
combination with ethinylestradiol- consider for women
who develop side effects like acne,headache,
depression, breast symptoms and BT bleeding with
other progestogens
 Desogestrel and gestodene -risk of VTE
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Drospirenone (Yasmin/YAZ)
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Derivative of spirinolactone
Antiandrogenic /antimineralocorticoid effect
Useful in
Acne/Hirsutism/premenstrual distrophic disorder
Thank You
Questions