Induction of Ovulation

in Ovulatory Cycles
(Is it a kind of malpractice?)

Salah Ali Sanad

Professor of Obstetrics & Gynecology
Cairo University
Ovarian stimulation is frequently used:
A) Empirically:
□ No pregnancy after a short period of marriage
□ Husband is available for a limited time
Nothing to lose
‫ما الذى سوف نخسره ؟‬

B) In unexplained infertility:
□ It is sometimes practiced, although no benefit
could be proved
 Items

1) Medication misuse (by physicians)

2) Are there any benefits for induction of
ovulation in ovulatory cycles?
3) Possible risks
Is ovarian stimulation in ovulatory cycles a form of
“MEDICATION MISUSE” ?

A) Inappropriate
Not following use
Drug
medical
misuse
instructions
B) Empirical
use
 A) Inappropriate use of medications

Not following the “five rights” of medication administration

1) The right patient

2) The right drug
3) The right dose
4) The right route
5) The right time
 B) Empirical Therapy
Based on experience
Definition:
Before confirmation of a definitive value
Advantage: possible in emergency conditions, eg covid-9
Drawbacks:
□ Safety aspect:
.. No drug is 100% safe (drugs are chemical substances)
.. No two people are exactly the same, each may respond
differently to a certain medication
□ Resource utilization inappropriately
 Items

1) Medication misuse (by physicians)

2) Are there any benefits for induction of
ovulation in ovulatory cycles?
3) Possible risks
Possible benefits in unexplained infertility
Rationale: greater number of ova per cycle increases the
chance of pregnancy
However
No evidence that induction of ovulation with timed
intercourse is more effective than expectant management-

Accepted ttt of unexplained infertility:

1) Ovarian stimulation alone ?? !!
2) Expectant management: timed intercourse & lifestyle
changes (↓ weight, stop smoking, ↓ caffeine..)
3) Ovarian stimulation with IUI
4) IVF
 Items

1) Medication misuse (by physicians)

2) Are there any benefits for induction of
ovulation in ovulatory cycles?
3) Possible risks
 Drawbacks
1) Multiple pregnancies: ovarian stimulation is the most
important cause of multiple pregnancies with
consequent LBW, increased miscarriage risk, IUGR & PTB
2) Possible increased implantation failure:
Studies have estimated causes of implantation failure:
□ One-third: due to embryo causes
□ One-third: due to poor endometrial receptivity
□ One-third: due to embryo-endometrial asynchrony
A- Endometrial harmful effect
B- The psychic stress (anxiety) caused by the procedure
C- Asynchrony between embryo & endometrium
3) Possible genomic imprinting defects
A- Harmful effect on the endometrium: which may worsen
endometrial receptivity:
1) By direct anti-estrogenic effect of drugs Open
on the endometrium (eg, clomiphene) receptor

2) By higher than the “normal appropriate physiologic”

estrogen levels which may possibly be harmful
to endometrial estrogen receptors Desensitized
receptor

Cellular action of a substance occurs by its binding to

cellular receptors in proper concentration & duration
More amount causes reduced or no effect
A) Desensitization = ↓ responsiveness
Through
B) Downregulation = ↓ No. of receptors
 Drawbacks
1) Multiple pregnancies: ovarian stimulation is the most
important cause of multiple pregnancies with
consequent LBW, increased miscarriage risk, IUGR & PTB
2) Possible increased implantation failure:-
A- Endometrial harmful effect
B- The psychic stress (anxiety) caused by the procedure
C- Asynchrony between embryo & endometrium
3) Possible genomic imprinting defects -
B) The psychic stress caused by folliculometry & timed
intercourse may increase implantation failure:

The psychic stress is closely related to

the functioning of the endometrium
Through
1- Uterine irritability (increased contractility)

2- Stress-induced endometrial dysfunction:

stress interferes with endometrial function:
□ By affecting endocrine hormones
□ By directly regulating the local endometrial
microenvironment
 Endometrial micro-environment

Endometrial changes are tightly controlled by:

A) Remote mediators: ovarian hormones
B) Local mediators: paracrine & autocrine
effect of morphogenes, cytokines &
growth factors, generated by all
endometrial constituents; epithelial,
stromal, local immune cells & the
vasculature
 Endometrial stress molecules
Have been found in the endometrium & share in
endometrial preparation
Types:
A) Hormonal: estrogen & progesterone-, as well as
adrenaline-related stress molecules
B) Neurogenic: stress-related neurogenic molecules
(neurotransmitters’ receptors) are present in abundance
• Monoamines (neurotransmitters) are important for endometrial
decidualization & blastocyst implantation
• MAO is important for endometrial preparation & increases in
endometrial glands & stroma during the receptive phase (considered
an important marker in esablishing endometrial receptivity)
 Effect of stress
(The physiologic stress response)
A) Activation of HPA axis through stimulation of the
sympathetic NS → catecholamine release (epinephrine
& norepinephrine) → production of CRH → ↓ LH &↓ E2
B) Inhibition of hypothalamic-pituitary-ovarian axis → ↓
frequency & amplitude of GnRH & LH pulses & a delay in
the LH mid-luteal surge
C) Increased proinflammatory cytokines which can alter
endometrial neurotransmitter signaling, gene
transcription & translation
Any factor that disturbs endocrine, paracrine
or autocrine signaling pathways that regulate
endometrial function might cause
endometrial dysfunction
 Drawbacks
1) Multiple pregnancies: ovarian stimulation is the most
important cause of multiple pregnancies with
consequent LBW, increased miscarriage risk, IUGR & PTB
2) Possible increased implantation failure:-
A- Endometrial harmful effect
B- The psychic stress (anxiety) caused by the procedure
C- Asynchrony between embryo & endometrium
3) Possible genomic imprinting defects -
 C) Possible embryo-endometrial asynchrony:

□ An ideal communication between the developing

embryo & the developing endometrium is critical for
successful embryonic implantation -
□ Implantation window is a short period of endometrial
receptivity which results from the programmed
sequence of the action of estrogen
& progesterone on the endometrium
 In natural ovulatory cycles
A more natural synchronized development
of the embryo & endometrium
should be attained than would occur with ovarian stimulation

With ovarian stimulation

Asynchrony might occur, due to
□ Rapid ovum (embryo) maturation, or
□ Advanced endometrial development (with premature
secretory changes) by more than the physiological levels
of E & P
 Drawbacks
1) Multiple pregnancies: ovarian stimulation is the most
important cause of multiple pregnancies with
consequent LBW, increased miscarriage risk, IUGR & PTB
2) Possible increased implantation failure:-
A- Endometrial harmful effect
B- The psychic stress (anxiety) caused by the procedure
C- Asynchrony between embryo & endometrium
3) Possible genomic imprinting defects -
 3) Possible adverse epigenetic effect
on the oocyte
□ ART babies have been shown to have more neuro-
developmental disorders like CP, intellectual disability &
ASD (systematic review & meta-analysis. Djuwantono T et al, J Neuro-
developmental Disorders, 2020)
□ Fertility drugs have been shown in many studies to ↑ ASD
.. Mechanism is unclear whether it is caused by the cause of
infertility or by a detrimental effect of the drugs on eggs
.. However, there is a high concern of the ability of these
drugs to cause genomic
genomicimprinting
imprintingdefects
defects
 Genomic imprinting defects

Genomic imprinting is an epigenetic phenomenon that

plays a critical role in normal embryo development

Epigenetics: heritable changes not caused by a change in

DNA sequence, but due to altered gene expression
How does this occur? by many mechanisms, the most
important is methylation-demethylation of genes
 Functions of Genes
1-Inheritance:
carry biological information from
one generation to the next

2-Morphogenesis:
tell each cell what to be

3-All biological functions:

according to the type of cell, through protein
production
 Genomic imprinting
Definition: “mono-allele expression” of some genes, i.e.
one of the two alleles from one parent is silenced, so
gene expression occurs only from one parent with
vulnerability to stresses because of no backup copy
Examples:
1) X-chromosome inactivation (Lionization)
2) ± 1% of somatic genes, several of which have important
roles in placental & embryo development (eg, IGF-2 &
cyclin-dependent kinase inhibitors)
Procedure: resetting (reprogramming) of genetic
expression occurs during gametogenesis
(spermtogenesis & oogenesis)
in three steps:
3
1) Erasure = demethylation - 3
2) Establishment = remethylation-
3) Maintenance of methylation -
Consequence of abnormal 2

imprinting: two active or two

1
inactive copies, causing
different
different gene
gene expression
expression
Abnormal imprinting in infertility treatment:
• In ICSI: there is increased incidence of some
syndromes in which genomic imprinting is involved,
eg Prader-Willi, Bekwith-Weidmann, Silver-Russel &
Angelman syndromes
• One of the explanations is that ovarian stimulation
accelerates ovum maturation allowing no enough time
for proper imprinting

Regarding autism,
due to the complexities involved in its causation,
it is very early to tell a definite statement, but
infertilitydrugs
infertility drugsmay
maybebeadded
addedtotothe
thelist
listof
oftriggers
triggers
 Conclusion

Proper use of drugs is of utmost importance

Empiric drug therapy has no place in Medicine,

except in emergency situations

Ovarian stimulation in ovulatory cycles is an

example of drug maluse
 Ovarian stimulation in ovulatory cycles

May affect ovum

May ↓ endometrial quality (may change
receptivity gene expression of
some genes)

May ↑ implantation failure &

possible log-term sequelae

So, ovulation induction should be used

only when properly indicated
 Thank you

?? Clomid 50
mg
Salah Sanad