Dr Thenmozhi Needhirajan DGO, MRCOGFellowship (University college London)Consultant Obstetrician and Gynaecologist

Kurinji Hospitals, CoimbatoreKarpagam Medical College, Coimbatore

Poole Hospitals NHS Trust, United Kingdom

My work in India 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

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

1st described by Irving Stein and Michael Leventhal as a triad of amenorrhea, obesity and hirsutism (1935)

The most common endocrine disorder in women of reproductive age ~ 2%-8% of women

Current suggested prevalence Caucasian: 4.8% African American: 8.0% Hispanic or Latino: 13% 5%-10% of women

Knochenhauer ES et al, Journal of Clinical Endocrinology & Metabolism, 1998.

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:– Thecal ( ovarian interstitial tissue) hypertrophy,leading to hyperandrogenemia– excessive activity of an enzyme called 17,20 lyase

CENTRAL HYPOTHESIS:abnormal GnRH pulse generation from thehypothalamus leading to abnormal, increased LHpulse amplitude and frequency

Clinical Features

Remember it is a syndrome, not a disease!

It’s the most common disorder of the

Endocrine system in women, 5-10%

Frequently begins around time of puberty

Strong genetic component, frequently a

family history of type 2 DM

Consensus Workshop

3rd PCOS consensus workshop- NetherlandsOct 2010•Adolescence•Hirsutism & Acne•Contraception•Menstrual cycle abnormalities•Quality of life and sexual health•Pregnancy complications•Cardiovascular & cancer risk

PCOS in Adolescence

• 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

• 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

Absence of longitudinal studies

Absence of specific diagnostic criteria

Absence of normative values for a number of

biochemical markers

Value of intervention

Unclear if the severity of the symptoms predicts

the extent of the disorder in later life

Hirsutism/Acne/Alopecia

• Hirsutism-Good marker for hyperandrogenism Present in 70% of women with PCOS

• Hyperandrogenaemia should be evaluated biochemically in all women

• Acne and Alopecia not commonly associated with hyperandrogenaemia

• 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

• 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/AcneLack 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

Menstrual Irregularity

• Women with PCOS may ovulate spontaneousely

• How frequent- unknown

• Oligo/amenorrhoea-90% chance of being diagnosed with PCOS

• Amenorrheic women- most severe hyperandrogenism/higher antral

follicle counts

• Menstrual cycles become more regular towards menopause

• Irregular periods are associated with increased metabolic risk

• 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

Treatment of Infertility

Weight loss 5-10% of body weight , 56%

had return of ovulatory cycles

Gonadotropin Therapy

injection of FSH to stimulate ovulation

Clomiphene - clomid

first line drugs

triggers ovulation in 80%,

Metformin

Metformin

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 abnormalitieso Scientific 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

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

Metformin vs Diane 35

Diane - decrease serum testosterone levels

Diane - worsening of glucose tolerance and decrease insulin sensitivity

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

Contraception

• 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

• 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

Head-to Head blinded trials comparing different OCP strategies are lacking

Lack of longitudinal FU studies after a course of OCPs

Quality of life (QOL)

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

Subfertility

Obesity,metabolic, inflammatory, endocrine abnormalities on ovulatory function,,oocyte quality and endometrial receptivity

Ovarian hyperandrogenism Hyperinsulinaemia –premature granulosa cell luteinisation – distrupt the intrafollicular environment- impairs cytoplasmic and nuclear maturation of oocytes

These features are not universal

Pregnancy

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

AN care should be closely monitored

Pregnancy associated risks are more in hyperandrogenic women

Babies may have increased morbidity and mortality

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 Should pregnancies of women with PCOS have

increased antenatal monitoring including earlier screening for GDM, additional dopplers

Long term outcome of children born from women with PCOS

Long term outcome for women with PCOS who develop GDM and gestational HT compared with women with PCOS who don’t conceive

Obesity

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)

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)

Risk assessment should be done periodically

Life long metabolic dysfunction in women with PCOS exaggerates CVD risk especially after menopause

All markers of CVD risk are higher in PCOS women

Endothelial dysfunction in PCOS is related to abdominal obesity and IR

Cancer risk

PCOS disrupts normal reproductive physiology

Increased risk of the development of CA endometrium

Moderate quality data to support 2.7 fold increased risk for endometrial CA.

Most are well differentiated with good prognosis

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

Majority contain ethinyl estradiol

Mestranol and Eastradiol valerate are also

used.

The dose varies from 20-40 micrograms

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 microgramsProgestogens(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

Drospirenone (Yasmin/YAZ)

Derivative of spirinolactone

Antiandrogenic /antimineralocorticoid effect

Useful in

Acne/Hirsutism/premenstrual distrophic disorder

Thank You

Questions