How are they different ??Difficulties & Solutions made Easy

Dr. Sharda JainDr. Jyoti Agarwal

Tremendous advances and extensive human studies have uncovered the complexity and

management of PCOD

Global prevalence -2.2% to 26% Roughly 1 in 15 women worldwide, (Lancet, 2007)

36% of women in India are suffering

from PCOS

Indian J Pediatr. 2012 Jan;79 Suppl 1:S69-73. J Pediatr Adolesc Gynecol. 2011 Aug;24(4):223-7

50 % presents with infertility50 % presents with recurrent miscarriages

PCOD is a Metabolic Syndrome with Huge Reproductive

Implications

Huge impact on the reproductive , metabolic , and

cardiovascular health of affected girls and women

THREE MAJOR CULPRITS Central player : Insulin Resistance• Hyperandrogenism • Altered Gonadotropins• Recently Target Genes

All interact with each other

Clinical manifestation of PCOD

Acne ObesityHirsutismAcantosis

InfertilityHAIR LOSSIRREGULAR MENSES

Her primary concern is

- INFERTILITY - Early pregnancy loss- She wants

Baby Baby Baby …

ObesityPre-Diabetes

Hypertension Fatty Liver

Diabetes type II Dyslipidemia

Insulin Resistance Hypo-Thyroidism

Metabolic Syndrome Vitamin-D deficiency

It is Good to rule out & counsel problems of …… before start

infertility treatment

Obesity is seen in more than 50 % of women with PCOS

Patients of BMI > 27.5 kg/m2 are likely to take longer to conceive

So it is good to lose weight by structured weight loss programme

Over weight BMI > 22.5Obese BMI > 27.5Severe Obese BMI > 32.5Morbid Obesity BMI >37.5

Methods of weight reductionfollow a pyramidal approach

• Diet and life style modification• Anti obesity drugs _ banned world wide

•Bariatric surgery (Definitely good option for severe and morbidly obese )

Diet management

Eat small meals at regular intervals Eat fruits, vegetables, beans,whole grains, fish, nuts and seeds in plentyLimit sugars and salt intakeAvoid saturated fats & carbohydrates

Early dinnerNothing in the mouth

after 7 pm

Daily moderate exercise for 40 – 60 min improves body's use of insulin and can help

relieve symptoms of PCOSRunning/Jogging

Chakki Chalanasana

Let zumba fitness Be your stress reliever &

An effective way to reduce weight

As little as 5% of initial weight loss over 6 months improves

fertility outcome

Sleeve Gastrectomy &Gastric Bypass surgeryare done routinely

Pregnancy should be delayed in the first year

Bariatric SurgerySignificant and sustained

weight loss of 40-50 kg is expected

FIRST LINECLOMIPHENE CITRATE

SECOND LINELOD/GONADOTROPINS

THIRD LINEIVF

RESISTANCE

RESISTANCE

FAILURE

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March 2–3, 2007, Thessaloniki, Greece.

Human Reproduction 2008

INFERTILITY GUIDELINE FOLLOWED WORLD OVER

AIM - Optimal Ovarian Stimulation for IVF

Be careful to :• Avoid understimulation• Avoid overstimulation• Minimize cycle cancellation• Avoid OHSS altogether

OI in PCOS is a big challenge

OPTIMAL STIMULATIONOVER STIMULATION

UNDER STIMULATION150

187.5

112.5

Drugs used to stimulate ovaries alone or in combination

• Clomiphene citrate

• LETOVAL/ANASTRIZOLE (ADDOVA)• Tamoxifen

Gonadotropins

Purified FSH Highly Purified FSH rFSH / RLH hMG

• LOD• IVF

Life style modification

Recommended First Line treatment for OI

remains Clomiphene Citrate

• Simple to use• Minimal side effects • Cost effective

Clomiphene citrate• Starting Dose 100mg

day 2 onwards for 5 days

• Max to 150 mg• If ovulation confirmed ,

maintain same dose

• Side effects• Hot flushes , bloating ,

dryness of vagina , headache , abdominal distension , visual symptoms ,and ovarian hyperstimulation

In the presence of visual problems (scotomas) CC should be discontinued promptly

Monitoring by serial sonography is a must

Are we happy with clomiphene ????

• 70% to 90 % will ovulate

• 40 % will become pregnant

• 75 % of conceptions occur during first three cycles

Yes

No

• Its antiestrogenic action causes poor / delayed endometrial growth and hostile cervical mucus

• Its presence at the time of ovulation inhibits progesterone formation by granulosa cells in luteal phase

• • Start early in cycle – Day 2 or Day 1

• Longer CC free peroid before ovulation

• Higher pregnancy rates

Clomiphene and ovarian malignancy

• When used only for 6 cycles , the risk of ovarian cancer will not exceed that of other women

But• More than 12 cycles of use in a life time is

associated with three fold increase in risk of ovarian cancer.

N Engl J Med 1994; 331(12):771-6

Options for women not responding to CC include

• Extended use of clomiphene citrate• Using letrazole , Anastrizole (ADDOVA) , Tamoxifen • Pretreatment with oral contraceptives• Adding dexamethasone in hirsutism hyperandrogenemia• Concomitant use of insulin sensitizers• Cabergoline in patients with hyperprolactenemia • Gonadotropins• Laparoscopic drilling

Off Label Drugs for OI

• Letrozole/Anasetrazole

non steroidal selective estrogen enzyme modulator

• Brings about monofollicular growth

• Prevents premature surge

Tamoxifen

• 20-40 mg/day x 5 days max 60 mg/day

• No anti-estrogenic effect on endometrium

• Ovulation rates 65 -75%

• Pregnancy rates 30 - 35%

Insulin sensitizers : MetforminCochrane review Jan 2008 : metanaylsis

• Metformin combined with CC is more effective in OI as compared with CC alone in obese & CC resistant cases

• Cheaper option than LOD• Co administration prevents

hyperstimulation

Metformin has an excellent safety profile , categoy B drug in pregnancy

• 500 to 850 mgm three times a day• S/E ….. diarrhoea, nausea, vomiting• To avoid them metformin should be taken

with meals and the dose increased gradually

• Monitor renal function

Evidence Based Medicine

• Use of metformin in PCOS should be restricted to those patients with glucose intolerance

ESHRE/ASRM-Sponsored PCOS Consensus Workshop *,2007, Thessaloniki, Greece

• Metformin may be added to CC in women with

clomiphene resistance who are older and have visceral obesity (I-A)

SOGC guidelines, 2010

Comparison in Asian women with PCOS

OI - 23.7 % Met alone - 59 % CC alone - 68 % in combined grp

PR - 7.9 % , - 15.4 %

- & 21.1 % respectively

Fertil Steril 2008

OTHER DRUGS WHICH CAN BE USED

• Rosiglitazone • Pioglitazone • Myo inositol• D chiro inositol• N acetyl cysteine• Combination with vitamin D3 and melatonin• Combinations with other micronutrients

NEEDS BIG RANDOMISED TRIALS

Gonadotropins : second line of Rx

Today recent advances and better technology has given us safe and effective gonadotropins with higher pregnancy rate , lower abortion rate and lower risk of hyperstimulation

• Effective daily dose of gonadotropins

• Age • Weight• Day 2 FSH• Antral follicle index• AMH

Dosage Of Gonadotropins Age PCOS-FSH

hyperresponderNormal responder

<30yrs 37.5/50/75 iu 150iu

30-35 yrs 75/100iu 150iu>35yrs 150iu 225iu

Which gonadotropins in PCOS?hMG OR recFSH

• Elevated LH is frequently encountered in PCOS • Excessive LH secretion with detrimental effects

on reproductive function• Use of FSH-only products rather than hMG

seems more logical

Balasch, Reproductive BioMedicine Online;February 2003

Days 7 14 21 28

hCG

150 IU 112.5 IU 75 IU hCG

Foll. 10 mm

75 IU112.5 IU 150 IU

6 12

75 IU hCG

Foll. 14 mm

½

Which Protocol should be used in PCOS ?

75 IU 112.5 IU 150 IUStep up

Step down

Sequential

LOD appears to be as effective as routine gonadotropin therapy in the treatment of

clomiphene-insensitive PCOS

Drilling of follicles releases androgen rich follicular fluid and decreases androgen producing stroma

Indications• CC Resistance• Pts. who persistantly

hypersecrete LH

Complications Haemorrhage, bowel

injury, adhesions, premature menopause

Results of therapies for ovulation inductionand pregnancy rate in pcos patient

Therapeutic option Ovulation % Pregnancy %

Multiple Pregnancy %

Spont . Abortion %

Clomiphene 80 40 8 – 10 20 – 25

Gonadotropin 80 -99 40 – 70 15 – 25 20 – 25

LOD 70 -90 44 – 66 2 20

Metformin+ Clomiphene

27 – 96(75)

30 – 60 (58)

_ _

33 – 50 % of patients will need IVF

Donot waste timeEarly referral should be in mind

IVF STIMULATION PROTOCOLS IN PCOS PATIENT

• Stimulation in PCOs is a problem

• Response is not predictable• Dose is not predictable• Poor responders/ hyper-

responders• Number of days of

stimulation is not predictable.• Decreased fertilization rate• Control over the cycle is

difficult.

RESPONSE OF PCOS TO STIMULATION

High order multiple pregnancy rate increased

OHSS is a Real Problem

Mortality due to critical OHSS in IVF

is totally Unacceptable DEVROEY 2011

44Dr Razia S

WE SHOULD ALL AIM FOR OHSS FREE ART CLINICS

We have given up Agonist protocol in PCOD patientsFragmentation of IVF

• All PCOD patients are taken for antagonist protocol to minimise risk of OHSS

• Ovulation triggering with GnRH agonist instead of HCG trigger

• Freeze all embryos & do ET in next cycle or do blastocyst transfer

Zero % OHSS

During pregnancy She is at high risk for

• Miscarriages• Gestational

diabetes• PIH• Preterm• IUGR / IUD

FIRST LINECLOMIPHENE CITRATE

SECOND LINELOD/GONADOTROPINS

THIRD LINEIVF

RESISTANCE

RESISTANCE

FAILURE

In conclusion