Management of

INFERTILITY in PCOD

Difficulties & Solutions

Made EasyDr. Sharda Jain

Dr. Jyoti Agarwal

Dr. Jyoti Bhaskar

Dr. Abhishek Parihar

Review this Lecture at:

Slideshare.net

Management of

INFERTILITY in PCOD

Difficulties & Solutions Made Easy

In Reproductive Age Group

Type of Patients Which We See

Anovulatory infertility

Obesity

Menstrual irregularity &

Heavy Menstrual Bleeding

For Prevention of

METABOLIC SYNDROME

Challenges of PCOD

In 20 - 40 yrs Age Group

WOMEN WORRY

• Infertility

• Early pregnancy Loss

• During pregnancy

- PIH

- GDM

Dr’s Worry

• Poor Ovarian Function

• Poor Oocyte quality & maturation

• High Insuline

• High Androgen

Treatment

Her concerns are

- INFERTILITY

- Early pregnancy loss

- She wants

Baby

Baby

Baby …

Not concerned about

Other Symptoms & Signs

in Adult Group

- Acne Hirsutism

- Metabolic Syndrome

• Central obesity

• Insulin resistance

• Glucose intolerance

- Ca Endometrium

Anovulation & Menstrual

irregularities

Obesity

PCOD & Infertility

Is our focus here As Lately it is confusing

The Gynaecologists !!

Learning Objectives

• Update on controlled ovarian induction.

• Update on follicle / cycle monitoring

• LOD

• Challenges of obesity / OHSS & multiple

pregnancy.

• Newer Drugs in PCOD

• Tailor Made Therapy

INCIDENCE :

Commonest endocrinal gynecologic disorder:

- Minimum 10% based on clinical

biochemical and u/s criteria in india

- 50-70% of Hirsutism.

- 80 - 90% of case of oligomenorrhea.

- great contribution to kitty of recurrent

miscarriage.

- 30% of infertility.

DIAGNOSISRef.http://www.slideshare.net/LifecareCentre/polycystic-ovarian-disease-hyperandrogenism-evidence-

based-update-on-diagnosis-consequences

Uploaded On slideshare.net

Acne

Obesity

HirsutismAcantosis

HAIR LOSSIRREGULAR

MENSES

Clinical Manifestation of PCOD

Bio chemical and Diagnostic

Markers of PCOD– Elevated androgen (i.e. testosterone > 60 or free

testosterone >0.75) levels

– Elevated LH:FSH ratio > 2:1

– Increased Insulin levels

– Insulin resistance , (Clinical / Lab)

Lab diagnosis of insulin resistance is not needed

– Ultrasound appearance of PCO

Accepted everywhere

Exclusion of Related Disorders

• Thyroid disorders

• Hyperprolactinemia

• Cushing’s syndrome

• Late onset congenital adrenal hyperplasia (CAH) \

• Basal morning 17-OHP,(2-3 ng/ml)

• Ovarian and adrenal tumors DHEAS

• WHO I &III –FSH,LH,E2

• Syndromes of severe insulin resistance(HAIRAN

syn)

Sr.TSH,Sr.Prl

Dexa supression test

TREATMENT OF PCOS in Adult Women

THIS CAN BE DIVIDED INTO TWO CATEGORIES

Women desirous

of pregnancy

Women not

desirous

pregnancy but

wants symptom

cure

Minimal Infertility Workup

• Semen Analysis

• Tube testing

•AMH

•R/O TB

Pre Treatment Considerations

• Weight loss

• Insulin Resistance

• Exclude Endometrial hyperplasia

• Exclude Metabolic Syndrome

Diagnostic criteria for various conditions are

not discussed here

BMI

Pre-Diabetes

Hypertension

Fatty Liver

Diabetes type II Hyperlipidemia

Insulin Resistance Hypo-Thyroidism

Metabolic Syndrome Vitamin-D Deficiency

It is good to RULE OUT

Diagnosis of following before

start of Treatment

Phenotypes of PCOS

1. PCOS with PCO :

• PCO + hyperandogenism + anovulation.

• PCO + anovulation.

2. PCOS without PCO :

hyperandogenism + anovulation.

3. PCO without PCOS.

( Isolated PCO = Asymptomatic PCO ).

(Azziz et al.,2006)

WHO

Classification

• I - Hypothalamic pituitary failure

(Hypogonadotrophic hypogonadism)

Kallman’s, Sheehan’s, anorexia

• II - Hypothalamic pituitary dysfunction

(PCOS)

• III – Ovulatory Failure –

Hypergonadotrophic hypogonadism,

Turner’s, autoimmune, mumps, RT, CT

FIRST LINECLOMIPHENE CITRATE

SECOND LINELOD/GONADOTROPINS

THIRD LINEIVF

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March 2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008

RESISTANCE

RESISTANC

E

FAILURE

THESSALONIKI CONSENSUS ON INFERTILITY

TREATMENT IN PCOS, GREECE 2007

THESSALONIKI CONSENSUS ON INFERTILITY

TREATMENT IN PCOS, GREECE 2007

Management in General

for PCOD Obese Patients

• Obese patients are advised to lose

weight which may

be accomplished by one or a

combination of following

methods -

– Diet

– Diet & Exercise

– Anti-obesity Medicines ???

Even 5% Weight loss improves

fertility outcome

Impacts Fertility Outcomes

Exercise

Daily exercise improves body's

use of insulin and can help

relieve symptoms of PCOS

A 30 minutes daily exercise can

improve many symptoms

COUNSELLING

• PCOS patients are often high

responders to medications

• Explain risk of

– Ovarian hyperstimulation syndrome

(OHSS)

– High risk of multiple pregnancy

– Possibility of fetal reduction

PCOD: Various treatment modalities for

infertility Treatment

Pharmacological Treatment Surgical Treatment

CC /Tomoxifen

hMG

uFSH

HP-FSH

rec-FSH

Gonadotropins

GnRH-analogs

Hyperinsulinemia?

Insulin sensitizer

Wedge

resection

LOD

Drugs for Ovarian Stimulation

in PCOS

• Clomiphene Citrate,

•Tamoxifen

• Gonadotrophins:

• HMG

• highly purified ur FSH

• Rec. FSH

• GnRH antagonist

•Metformin

CLOMIPHENE CITRATE

• Most widely

• Simple to use,

Minimal side effects,

Cost effective

CLOMIPHENE CITRATE ( SERM)

HYPOTHALAMUS ER

Binds

GnRH

Pituitary

FSH

OVARY

Folliculogenesis

Blocks ER

Cervix

Endometrium

Vagina

DOSAGE

• Single dose -- together

• Monitor Cycle with USG

• If ovulation confirmed – maintain same

dose

• Max to 150 mg

Starting Dose 100mg day 2 onwards for 5 days

Anovulatory infertility in PCOS

50-80% will ovulate on CC

Only 40-50% will conceive

CC FAILURE ( 40%)

No Pregnancy 3 CYCLES OF CC

WITH OVULATION AND TIMED INTERCOURSE

2 CYCLES OF CC WITH IUI

CC RESISTANCE (20%)

3 CYCLES OF CC

NO OVULATION

CC +GONADOTROPHINS

GONADOTROPHINS

COST , PT’S CHOICE

COUNSELLING

Antioestrogenic Effect

• Thin Endometrium

• Poor Cervical Mucus

Start early in cycle – Day 2 or Day 1Add oestradiol valearate from day 8/9

Use all gonadotrophin cycle

BIGGEST Breakthrough

Enclomiphene citrate versus clomiphene citrate

as a primary ovulation induction drug in Type -2

anovulatory infertility cases (PCOD) as per WHO

Results

Better Ovulation Induction

Better Endometrial thickness and

An edge in pregnancy rate

Indian market is flooded with such preparations

TAMOXIFEN

• 20-40 mg/day D2- D7,max 60 mg/day

• Off label use for OI

• Ovulation rates- 65 to 75%

• Pregnancy rates- 30 to 35%.

• Advantage-

– No anti-estrogenic effect on endometrium.

– Improve bone density & lipid profile

• 2-3 times increased risk of endometrial Ca & DVT

• No evidence of a difference in effect between CC

and tamoxifen (Cochrane library, 2009)

INDICATIONS FOR METFORMIN

IN PCOS

• Weight loss with lifestyle changes

• Menstrual disorders

• Anovulation resistant to CC

• IGT /Type II DM

• Metabolic syndrome

METFORMIN—PRESENT ROLE

• 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

OCTOBER 2010

IS METFORMIN INDICATED AS PRIMARY OVULATION

INDUCTION AGENT IN WOMEN WITH PCOS? A SYSTEMATIC

REVIEW AND META-ANALYSIS

• CC alone is superior to M alone regarding

live birth rate and Ovulation.

• An increase in ovulation and pregnancy

rate with CC+M when compared with CC

alone , but no difference was found when

live birth rate

Siebert T.I. Viola M.I Steyn D.W. Kruger T.F 2012

Tygerberg Hospital

INSULIN-SENSITISING DRUGS (METFORMIN, ROSIGLITAZONE,

PIOGLITAZONE, D-CHIRO-INOSITOL) FOR WOMEN WITH POLYCYSTIC

OVARY SYNDROME, OLIGO AMENORRHOEA AND SUBFERTILITY

• Metformin was associated with improved clinical pregnancy but there was no evidence that metformin improves live birth rates whether it is used alone (or in combination with clomiphene when compared with clomiphene.

• Therefore, the role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.

• Metformin was also associated with a significantly higher incidence of gastrointestinal disturbances than placebo (

Cochrane library:16 may 2012(up-to-date: 2 oct 2011)

METFORMIN TREATMENT BEFORE AND DURING IVF OR

ICSI IN WOMEN WITH PCOS

• No evidence that metformin treatment before or

during ART cycles improved live birth or clinical

pregnancy rates. The pooled OR for live birth rate (3

RCTs) was 0.77 and for clinical pregnancy rate (5

RCTS) was 0.71.

• The risk of OHSS in women with PCOS and

undergoing IVF or ICSI cycles was reduced with

metformin

Cochrane library: 2009

PCOS Patients with

Anovulation & Ovulation disorder

RESISTANT TO CLOMIFENE CITRATE:

SECOND – LINE TREATMENT, depending on clinical circumstances and the women’s preference

• Gonadotrophines

• Laparoscopic Ovarian drilling or

(NICE 2013)

Gonadotrophins - Indications

CC Resistance

CC Failure

• HMG

• Highly purified Urinary HMG/FSH

• Recombinant. FSH

Choice of Gonadotrophins

Day 2 LH/FSH

FSH

LH

PCOS

FSH

WHO group1

HMG

DOSE

• BMI

• Ovarian reserve

• Age

• Cause of Infertility

• Dose needed in previous cycle

Complications

Multifetal pregnancy

• OHSS - Life threatening

MonitoringExperience

Strict protocols

1. CC only with TI or IUI

2. CC ± FSH or ± HMG with IUI

3. Gonadotrophin only

n Conventional regime

n Gn. Low dose step-up protocol

n Gn. step-down protocol

4. Gonadotrophin with GnRH antag

Protocols

2

3

4

5

6

7

8

9

10

11

12

13

14

15

21

DAYS OF CYCLE

TVS – ET AND AFC

CC

100 MG

DAILY

Day 2-6

TVS – FOLLICLE SIZE, ET

IF ET< 5MM OV 2MG BD DAILY

TVS – FOLLICLE , ET , CERVICAL MUCUS

STUDY, POST COITAL TEST

FOLLICLE >20MM -- LH SURGE

+ VE -VE

Inj HCG 5000 U i/m

Timed Intercourse

8pm stat

IUI

36 hrs later at 8am at Lifecare24hrs later at 8am

Sexual relation at same night and for 2 days

Luteal support – ETV ES/ Susten vaginally at night

Serum Progesterone 7 days after IUI/Ovulation

CC ONLY PROTOCOL -- +/- IUI

B LONG F ONCE DAILY ALL

THROUGH OUT THE CYCLE

UPT 18 days after IUI/Ovulation

Unripe follicle

Ripening follicle

Ovulation Corpus luteum

Regression of Corpus luteum

Clomiphene

100 mg day2

for 5 days

Gonadotrophin

stimulation

HCG Leading follicle > 18mm

Oocyte mature

38 hrs

75 IU 75 IU 112.5 IU 150 IU

Days 7 14 21 28

hCG

Chronic Low Dose (CLD): S. Franks et al.

Step Down (SD): B. Fauser et al.

Sequential (SE): J.N. Hugues et al.

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

FSH Administration Regimens

LAPAROSCOPIC

OVARIAN DRILLING

Laparoscopic Ovarian Drilling

• Main Indications

1. CC Resistance

2. Pts. who persistantly hypersecrete LH

• Methods – Monopolar cautery or Laser

• Efficacy

50% of LOS treated Pts. adjuvant therapy will be reqd.

Addition of CC after 12 weeks if no ovulation detected

Addition of FSH should be considered after 6 months.

• Complications

Haemorrhage, bowel injury, adhesions, premature menopause

MECHANISM OF ACTION

A.) Drilling of follicles releases androgen rich follicular fluid and

decreases androgen producing stroma.

B.) There is transient reduction in inhibin and precipitous fall in LH, which increases secretion and expression of FSH.

C.) Crowding of cortex decreases which allows progress of normal follicles to the surface resulting in resumption of normal ovulation.

LOD appears to be as effective as routine gonadotropin therapy in the treatment of clomiphene-insensitive PCOS.

LAPAROSCOPIC OVARIAN DRILLING (LOD)

Advantages

• High success rate

• Prolonged response

• ↓Multiple births

• ↓ OHSS

Disadvantages

• Adhesion formation

• Requires surgery

• 1/3 require ovulation medications

• POF risk

• Less successful in smokers 25% vs 95%

Technique: 4 puncture/ovary,4-5 mm depth,40 watt

coagulation for 4 sec

PATIENTS RESISTANT FOR LOS

• Increased duration of infertility (>3yr)

• Women with marked obesity,

BMI>35kg/m2

• Increased free testosterone and free

androgen index

Practical tips for monitoring for

ovulation induction in PCOS

Do it yourself

Who Should Monitor?

Why Add to The Burden ?

Five Reasons To Monitor

To evaluate if the dose being used is optimal

To adjust the dose of the drug as some patients

are hyper responsive and some are poor

responders.

To find the optimal time for inducing ovulation

To time IUI

To avoid excessive stimulation , to prevent OHSS

and multiple pregnancyAll patients to be monitored

How to Monitor ?

• BY E 2 ALONE

• BY ULTRASOUND ALONE

• BY BOTH

• BY COLOR POWER DOPPLER

• BY OTHER HORMONES

MINIMUM MONITORING

MonitoringUltrasound states the morphological

growth of the follicles

Hormones indicates the functional

activity of the follicles

Monitoring Should Be

• Easy

• Reliable

• Patient friendly

• Not expensive

• Can be done by self

Importance of D - 2 Scan

TVS is performed on day 2 of the cycle to see for

• Antral follicle count• To rule out any cyst.( > 3 cm)• Endometrial shedding• Or any other pelvic pathology

We expect normal sized ovaries with very small follicles(3—5 mm in diameter)

Follicles are of clinical importance only when their size is 10 mm

Follicular size is measured by taking mean of 2 or 3 largest perpendicular diameters of each follicle .

Ultrasound Follicular Monitoring

Serial USG follicular monitoring is started fromday 7 or 8 of the cycle

But in case of gonadotrophins we start scanning from 6th day of stimulation.

Assessing the Follicular Maturity

• The follicles normally grow at a rate of

2- 3 mm / day in a stimulated cycle.

• Definitive size of the follicle which confirms

the maturity of oocytes is still controversial.

• A follicle measuring 18—20 mm has been

found to contain a mature oocyte.

Correlation with serum

oestradiol levels

• Plasma estradiol levels correlates closely with the stage of development of the dominant follicle

• Serum estradiol levels >200 pg / ml on day 8 of stimulation indicates adequate dose of gonadotropins.

Ultrasound monitoring has totally replaced estradiol monitoring in most centers.

Follicular Doppler

Flow Studies

• A mature follicle shows vascularity in atleast ¾ th of the follicular circumference &

• PSV is 10 cm/sec.

• At this time LH surge starts and

• This is the right time to give hCG trigger

Interpretation of Ovarian Indices

• Rising PSV & steady low RI suggests follicle is close

to rupture

• Decreasing PSV & rising RI suggests follicle is likely

to become LUF.

• Fertilisation of a follicle with PSV of less than 10 cm

/sec may result in an embryo with chromosomal

abnormality.

Perifollicular vascularisation

Grade 1 : < 10% Grade 2 : 10-25%

Grade 3 : 25-50% Grade 4 : > 50%

hCG timing

ALWAYS TIME HCG WITH FOLLICLE SIZE

Ovulation TriggerThe end point of any ovulation induction

protocol is to indentify the best time for

triggering ovulation.

most crucial step

In a gonadotrophin In clomiphene

Leading follicle is Leading follicle is

18 – 20 mm in diameter. 20 – 22 mm in size

Ovulation to Be Confirmed By

• Disappearance of the follicle

• Presence of free fluid in the cul-de-sac.

• Presence of hyperechoic , smooth

secretary endometrium.

Timing of insemination

IUI is done 24 hrs. after LH

surge is detected

IUI is done 36 - 38 hrs. after

hCG injection

Serum Progesterone and

Implantation

• Periovulatory progesterone levels are used

as a predictor of outcome.

• Elevated levels of serum progesterone in the

late follicular phase is associated with

diminshed chances of conception.

Premature LH surge

• Premature LH surge is known to occur in

approx 25 % of patients once the leading

follicle is 16 mm.

• Urinary LH kits are available to detect LH

surge.

A blood level of >10 IU /L correlates with the LH surge

Premature LH surge

• If an LH surge is detected , injection hCG is

given immediately.

• The hCG injection is required to supplement

the LH secreted by the body as it is not

adequate enough to induce the final

maturational changes in all the follicles .

• IUI is done 24 hrs after the LH surge

• Over 50 % of women under 40 years

will conceive within 6 cycles of IUI

• Of those who do not conceive within 6 cycles of IUI about half will do so in next 6 cycles

Chances of Conception in

PCOD in IUI cycles

Cumulative pregnancy rate is

over 75 %

NICE guidelines 2013

Important !!!!

Clinics providing ovarian stimulation with gonadotrophins should have protocols in place for

-Preventing

-Diagnosing OHSS-Managing

NICE guidelines 2013

Challenges in PCOD & Infertility

OBESITY

OHSS

UPLOAD ON SLIDESHARE.NET

Obesity

And

Female Infertility

Ref : http://www.slideshare.net/LifecareCentre/obesity-in-

female-infertility-by-dr-sharda-jain-dr-jyoti-agarwal-dr-jyoti-

bhaskar-dr-abhishek-parihar-dr-yogesh-agarwal

Uploaded on slideshare.net http://www.slideshare.net/LifecareCentre/medical-management-of-

ovarian-hyperstimulation-syndrome-ohss-in-1500-iui-cycles-

practical-tips

Ovarian Hyperstimulation Syndrome (OHSS)

Practical Management

In 1500 IUI Cycles

PCOSTreatment Guidelines

&

Review of

Newer Medical Treatment in Infertility

Uploaded on slideshare.net

Ref. http://www.slideshare.net/LifecareCentre/pcos-treatment-guidelines-

review-of-newer-medical-treatment-in-infertility-dr-sharda-jain

Newer concepts of managing

With Myo-Inositol

Uploaded on slideshar.net

Ref: http://www.slideshare.net/LifecareCentre/newer-concepts-

of-managing-pcod-with-myoinositol

Summary of

Uses of Newer Drugs

TAKE HOME MESSAGE

• Preconceptional counselling

• Recommended first line treatment-Clomiphene

• Metformin in CC resistant & BMI>30 kg/m2

• Second line: Gonadotropins or LOD

• LOD pregnancy occurs in about 50% cases, it

also decreases Dose of additional ovulation

drugs required

• Third line: IVF our challenges & experiences will be uploaded shortly

ADDRESS 11 Gagan Vihar , Near Karkari Morh

Flyover Delhi -51

CONTACT US

9650511339

011-22414049,

WEBSITE :

www.lifecarecentre.in

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E-MAIL ID

Sharda.lifecare@gmail.com

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info@lifecareivf.com