Dr Sohani Verma

Sr. Consultant Obstetrics & Gynaecology

Infertility & ART Specialist
Clinical & Academic Coordinator
Indraprastha Apollo Hospitals, New Delhi
Chairperson North Zone AICC RCOG
President Elect Indian Fertility Society

Introduction
A woman of reproductive age who has not conceived
after 1 year of unprotected vaginal sexual
intercourse, in the absence of any known cause of
infertility, should be offered further clinical
assessment and investigation along with her partner.

Offer an earlier referral for specialist consultation to

discuss the options for attempting conception,

further assessment and appropriate treatment where

- the woman is aged 36 years or over

- there is a known clinical cause of infertility or a
history of predisposing factors for infertility
NICE Guidelines 2013

Main Causes of
Infertility

Multiple relatively minor abnormalities, either with 1 partner or both,

account for 30% of all causes

Assisted Reproductive Techniques

(ART)
Any treatment that deals with means of
conception other than vaginal intercourse is
termed as ART.
NICE guideline 2013

IUI Intra Uterine Insemination (Husband /

Donor)
IVF + ET In Vitro Fertilization + Embryo transfer
ICSI Intra Cytoplasmic Sperm Injection

IUI

Injection of washed prepared sperms into

the uterine cavity through a fine catheter
during peri-ovulatory phase in a natural
or stimulated cycle.

Although pregnancy may not occur as quickly, a

policy of initial treatment by IUI will probably save
20% of couples from moving onto IVF

After 3-4 cycles of failed IUI treatment,

patients should be encouraged to opt for IVF

IUI

The procedure may help in increasing the chances of

pregnancy in following ways
1.Allowing sperm-ovum contact close to the date and time
of ovulation
2.By bringing the sperm very close to the site of
fertilization and by passing the cervical factors
3.Sperm preparation increases the sperm density and
removes all antigens on the surface of sperm and in
seminal plasma
-IUI is the simplest and the least expensive method
of ART
-IUI alone (natural cycle) does not improve
pregnancy chances, hence mild ovarian stimulation
is usually recommended.

Indications for Intra Uterine

Insemination (IUI)
- At least one Fallopian tube must be normal
and
patent
- Mild male infertility
- Unexplained infertility
- Ovulatory dysfunction, PCOS
- Mild endometriosis
- Cervical factors
- Coital problems
- Immunological factors
- HIV, HBs Ag infection
- Donor Sperm

Indications for Donor Sperm IUI

Azoospermia

(where ICSI is not an

option)
Severely subnormal semen parameters
(ICSI not an option)
Persistent failure of ICSI
Rh Isoimmunization
Hereditary disease in the male partners

Indication for ART IUI or IVF

The indications for IUI are

often not dissimilar to those

for IVF (or even for ICSI for
moderate male factor) and
often interchangeable with
overlapping.

Common Indications for IUI

IVF

Indications for

-Unexplained infertility
-Endometriosis (mild)

- Unexplained infertility
- Endometriosis (moderate to severe)
-Male factor infertility (mild)
- Male factor infertility
(moderate to severe)
-Ovulatory disorders - Ovulatory disorders
-Inability to have vaginal intercourse
-People with conditions that require

Tubal pathology
- Donor Oocyte

specific consideration (such as man HIV

positive)
- Genetic Surrogacy
- People in same-sex relationship
- PGD (Possibility of
genetically
- Donor Sperm
transmitted disease)
Fertility preservation in cancer
patients
- Where ICSI is indicated
(Azoospermia)

Meta-Analysis of IUI in Male Factor

Pregnancy Rate
Timed intercourse in natural cycle
Timed intercourse in COH cycle
IUI in natural cycle
6.5%
IUI in COH cycles
12.6%

2.4%
5.0%

Cohlen BJ et al Cochrane database Syst Rev 2003

Basic requirements for IUI

success

1. Patient selection
- Age of female partner < 35 years
- Duration of infertility < 5 years
- Cause of infertility (at least one functional normal

fallopian tube and no uterine factors)

- Adequate ovarian reserve (based on Serum AMH, antral
follicle count, Day 2 FSH, LH, E2 levels)
- Semen parameters Post wash TMSC >5 million/ml
Best pregnancy rates with >10 million/ml
< 1 or 2 million/ml do not waste time in
IUI.
Advice IVF / ICSI straight away

Basic requirements for IUI success

contd

2. Choice of ovarian stimulation used

3. Number of dominant follicles 1 to 3 follicles
4. Use of transvaginal ultrasound follicle

monitoring
5. Timing of IUI
- Between day 12 to 16 of the cycle usually
highest pregnancy rates
- Interval from hCG injection 32-42 Hours usually
recommended (range 12-60 hours)
- Single IUI 36 hours after hCG is usually the
preferred option.

Basic requirements for IUI success

contd

6. Semen preparation technique Quality

and expertize of lab personnel

7. Procedure of IUI & type of catheter used
8. Luteal support is recommended
9. How many IUI cycles- 3-6 cycles usually
recommended

INTRAUTERINE INSEMINATION ESHRE

Guidelines
There is general agreement in the literature that chances
of success are better after mild ovarian stimulation
and the maturation of a maximum of two or three
follicles.
However, the cycle must be monitored by ultrasound
and hormonal analysis; if there are more than three mature
follicles, the attempt should be cancelled.
While the concurrent use of ovarian stimulation may
increase pregnancy rates, it may be at the expense
of a high chance of multiple pregnancy.
The majority of pregnancies occur during the first six
cycles. In any case, the number of attempts should not
exceed nine cycles.
When assessing the duration of an IUI programme, the age
of the woman must be taken into account, to ensure
timely transfer to more complex treatments if indicated.

 The world's first "test-tube

baby", Louise Brown, has
spoken of her joy at giving
birth to her first child.

Baby Cameron was born on

20 December06 in Bristol,
where his 28-year-old mother
lives with husband Wesley
Mullinder.
Well over two million "test-tube" babies have been born globally
since Louise's 1978 birth after IVF

IVF and ET

In Vitro Fertilization (IVF) and Embryo Transfer (ET) are the basic ART
for all related technology. These include:
-

Intra Cytoplasmic Sperm Injection (ICSI)

Assisted hatching

Pre-implantation Genetic Diagnosis (PGD)

Cryopreservation

Donor oocyte IVF programs

Donor embryo (genetic surrogacy)

Intracytoplasmic Morphologically selected

Sperm Injection (IMSI)

And many more

Pre IVF work-up

Ovarian stimulation

Monitoring

Preparation of
sperms

Oocyte retrieval

Ovulation induction

In Vitro Fertilization

Embryo transfer

Luteal Support

IVF & ET
Procedure
Picture

In vitro embryo
development

COC at the time of

retrieval

4 cell embryo

M II oocyte with a
PB (Mature)

8 cell embryo

2 PN embryo

Fully grown
blastocyst

Indication for IVF

I. IVF as first line infertility treatment
- Tubal pathology (severe, non-repairable)
- Donor Oocyte
- Genetic Surrogacy
- PGD (Possibility of genetically transmitted disease)
- Fertility preservation in cancer patients
- Where ICSI is indicated (Azoospermia)
II. IVF following failed cycles of IUI
-Usually up to six cycles of IUI with controlled
ovarian stimulation are recommended, but there are
situations where couples should move to IVF earlier.

Indicators for early referral

I. Female age
- The biological clock is the major adversary
to human
reproduction

Womans age is the initial predictor of

her overall chance of success
Live birth rates per
Embryo transfer by age
(HFEA post-October
2007 data)

NICE Guideline

II. Diminished Ovarian Reserve at any age

- AMH- anti-Mullerian hormone of less than or

equal to
5.4pmol/l
-Antral Follicle Count (AFC) Less than or equal
to 4
-Day 2/3 FSH >8.9 IU/L
III.Endometriosis
IV.Moderate (more than slightly abnormal) degree

of semen quality abnormalities.

V. Tubal Compromise
NICE Guideline 2013

ICSI

Unprecedented
successful
development of ART
which has
revolutionized the
management of
severe male
infertility (Van
Steirte-ghen 1992)

The procedure
involves the direct
injection of a

Indications for ICSI

- Severe alterations of semen characteristics
- History of fertilization failure in conventional IVF

attempts
- Testicular or epidydimal sperm
- Other relative indications

Success rates following IVF /

ICSI
24.7

percent clinical pregnancies of all women

who undergo IVF treatment (HFEA 2011).

50%

of all embryos cultured in vitro reach

blastocysts stage by day 6.

About

15% of transferred embryos will develop

into a baby

Basics requirements for IVF/ICSI

success
1. Pre IVF work up of the infertile couple

Clinical history
Examination
Investigations
Counseling
Why necessary?

To identify the cause of infertility and thereby prognosis

To identify and correct associated adverse factors before treating

primary disorder
To decide most appropriate treatment protocol

- Type of drug
- starting dosage
- expected response and problems

To assess reproductive ageing and plan early access / resort to

ART treatments

2.

Basic requirements for IVF/ICSI

success contd

To get adequate number of good quality oocytes

A. Predictors of COHS response

- Age, AMH, AFC

- Response to earlier COHS
- Basal FSH, LH, E2
- BMI, Smoking, Alcohol
- Previous Ovarian Surgery
B. Selection of COHS protocol
- Agonist versus Antagonist protocols
- Mild stimulation protocols

Normal responders
Hyper responders
Hypo- responders

Basic requirements for IVF/ICSI

success contd

C. Ultrasound monitoring with power and colour

Doppler
D. Biochemical Monitoring
2. Ovulation induction
- hCG - urinary / recombinant
- GnRh agonist
3.Technique of Oocyte retrieval
4.Embryology lab quality and expertize
5.IVF or ICSI
6.Selecting best embryo (s) for transfer
7.Number of embryos transferred
8. Embryo transfer technique
9.Luteal Support

Luteal
Support

Luteal Support
The

transformation of mature follicle into corpus

Luteum (CL) after the release of ovum is
triggered by an optimal LH surge.

The

function of CL is dependent upon

continued LH stimulation in luteal phase.

CL

is an essential source of pro-fertility

hormones ie Progesterone (P), Estrogen (E) and
other vasoactive and growth factors.

Luteal Support
It is well established that the ovarian

stimulation regimens used in assisted

reproduction cycles alter the luteal phase.
et al 2003

Edwards et al 1980, Kolibianakis

Ovarian stimulation causes

- an inadequate development of the endometrium
- an asynchrony between the endometrium and the

transferred embryo and

- adverse effects on endometrial receptivity
2004

Macklon & Fraser 2000, Devroey et al

Luteal Support
contd
The luteal phase defect in IVF is present

whether GnRH agonist or antagonist is used

(Friedlers et al 2006).
The possible mechanism responsible may
be
- Continuation of pituitary down regulation effect
- Duration of luteal phase is shortened
- Formation of multiple CL leading to inhibition of
pulsatile LH release
- Loss of granulosa cells during oocyte retrieval

Luteal Phase Support

I. Endometrial support complements production

by CL
(i) Progesterone preparation
(ii) Estrogen preparation
II. Agents which support CL
(i) hCG
(ii) GnRH-analogue
(iii) LH
III.Newer agents which promote angiogenesis and

vascular supply

Progesterone preparations
available
(i) Micronized
(a) Oral / vaginal
(b) Vaginal Gel (8%)
(c) Vaginal Pessary
(ii) Intramuscular (oil based)

- 200-400 mg BD
- 90 mg daily
- 100-400 mg daily
- 100-400 mg

daily
(iii) Subcutaneous (aqueous preparation) - 25 mg daily
(iv) Synthetic Dydrogesterone
or TDS

10 mg BD

Estrogen as an adjuvant
to LPS

Estradiol valerate.

Hemihydrate
- Oral (intravaginal)
- 2-6 mg/day
Micronized Estradiol
- Oral or intravaginal
- 2-6 mg/day
Transdermal Estradiol
- Patches (2 per week)
- 50-100 ugm/day

GnRH agonist as an adjuvent to

LutealLPS
Phase Support for assisted reproduction
cycles (Cochrane Review 2011)
- Tesarik J et al 2006 published their result on 600

women randomly assigned to receive a single injection

of GnRH agonist (0.1 mg of triptorelin) or placebo on
Day 6 after ICSI. The results showed improvement
of implantation and live birth rates.
- Van der Linder et al investigated progesterone versus
prog + GnRHagonist
- Six studies (1646 women)
- There were significant results showing a benefit
from addition to GnRH agonist to progesterone
for the outcomes of live birth, clinical pregnancy
and ongoing pregnancy.

Luteal Phase Support for ART Cycles

Authors' conclusions
Cochrane Review
Cochrane review 2011 showed a significant effect2011
in favour of
progesterone for luteal phase support, favouring synthetic
progesterone over micronized progesterone. Overall, the addition of
other substances such as estrogen or hCG did not seem to improve
outcomes.
They found no evidence favouring a specific route or duration of
administration of progesterone.
It was found that hCG, or hCG plus progesterone, was associated with
a higher risk of OHSS.
The use of hCG should therefore be avoided.
There were significant results showing a benefit from addition of
GnRH agonist to progesterone for the outcomes of live birth, clinical
pregnancy and on-going pregnancy.
For now, progesterone seems to be the best option as luteal phase
support, with better pregnancy results when synthetic progesterone is
used.

Nutritional Supplements and ART

outcome
No definite conclusive evidence
Anti-oxidants

Vit C, E, selenium, zinc, taurine,

carotene, lycopene
Vitamins Folate, Vit B 12
Myoinositol and D-chiro-inositol (vit B complex)
L Arginine
DHEA

Dehydroepiandrosterone (DHEA)
supplementation
Cason and associates (2000) were first to suggest therapeutic benefits

from the supplementation of DHEA in women with diminished ovarian

reserve and suggested it may improve oocyte yields via IGF-1.
It was left to a 43 year old infertility patient in US (advised donor

oocytes) to discover their paper and self administer DHEA while

undergoing subsequent IVF cycles.

The patient underwent

nine consecutive IVF
cycles and increased
oocytes and embryo
yields from cycle to cycle,
starting with one egg and
embryo, respectively,
and ending up with 17
oocytes and 16 embryos
in her ninth cycle.

Dehydroepiandrosterone (DHEA)
supplementation
While all other pharmacological agents affect follicle

maturation only during the final stage gonadotropin

sensitive last 2 weeks, DHEA in contrast appears
to affect folliculogenesis at much earlier stages
of in-vivo follicle maturation (Gleicher N etal 2011)
DHEA has been shown to increase the number of

primary, preantral and antral follicles.

DHEA supplementation is reported to improve

ovarian response, IVF parameters and

pregnancy chances. Younger patients with POA
appears to have a slight pregnancy advantage.

Cumulative pregnancy rates in women with DOR with and without

DHEA supplementation. POA patients appear to have a slight
pregnancy advantage, Barad et al 2007

DHEA supplementation is also shown to significantly

(50-80%) reduce the miscarriage risks in patients with
poor ovarian reserve
(Gleicher etal 2007)

Age-stratified miscarriage rates in DHEA supplemented DOR

patient in comparison to national U.S. IVF pregnancies. Gleicher
et al 2009

Treatment protocols, side effects and

complications
Micronized DHEA at a dosage of 25mg TID
Effects occur relatively quickly (6-8 weeks) but peak

only after 5-6 months of supplementation.

Side effects are small and rare and primarily relate to
androgen effects oily skin, acne vulgaris and hair
loss.
Even long-term therapy of DHEA in suggested
dosages have been demonstrated safe (Panjari M
etal 2009).
However, before declaring DHEA as a wonder
drug, larger RCTs are urgently needed to
confirm the benefits.

Sohani