Date post: | 15-Jan-2016 |
Category: |
Documents |
Upload: | david-webb |
View: | 249 times |
Download: | 1 times |
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