Polycystic ovarian syndrome

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Polycystic ovarian syndrome

• 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

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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

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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

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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.
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What is PCOS?

• A chronic condition characterized by
• anovulatory infertility,
• hyperandrogenism , hyperinsulinaemia, insulin
  resistance
• with clinical manifestations of
• oligomenorrhoea,hirsutism and acne

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Definition

• 1990 NIH DEFINITION
• 1. OLIGOMENORRHEA
• 2. HYPERANDROGENEMIA
• 3. Absence of other disorders such as
• NCAH, Hyperprolactinemia, thyroid
• dysfunction.

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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

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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 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!
• Its 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

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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

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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

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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

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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

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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

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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

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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

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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/hi
  gher 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

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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
• Gonadotropin Therapy
• injection of FSH to stimulate ovulation
• Clomiphene - clomid
• first line drugs
• triggers ovulation in 80,
• Metformin

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Metformin

• Metformin PCOS
• JCEM 2000 Italy (Moghetti et al)
• N23 PCOS (mean BMI 30)
• Randomized - Metformin 500 tid or placebo x 6
  months
• Androstenedione, 17OHP, estradiol, SHBG, lipids
• OGTT, insulin sensitivity with glucose clamp

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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
• 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

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Metformin vs Diane 35

• JCEM 2000 Finland (Morin-Papunen et al)
• N 32 (BMI gt 27)
• Metformin 500 bid x 3m --gt 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
• Diane - worsening of glucose tolerance and
  decrease insulin sensitivity
• Metformin possibly superior to Diane specially
  if fertility is a concern

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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

• 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

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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)

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Contraception - Knowledge gaps

• Head-to Head blinded trials comparing different
  OCP strategies are lacking
• Lack of longitudinal FU studies after a course of
  OCPs

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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

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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)

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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

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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

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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)

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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 dont conceive

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Obesity

• Widespread variability in the prevalence of
  overweight (BMI 25-30 ) and obese(gt30)
• 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

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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

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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

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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

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Menopause

• Age may improve many manifestations of PCOS
  including normalizing ovarian size and
  morphology, T levels and oligo-ovulation prior to
  menopause

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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

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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)

• Derivative of spirinolactone
• Antiandrogenic /antimineralocorticoid effect
• Useful in
• Acne/Hirsutism/premenstrual distrophic disorder

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• Thank You
• Questions