This document discusses ovarian stimulation using clomiphene citrate. It notes that estrogen is the main hormone that regulates gonadotropin production, so clomiphene citrate acts as a selective estrogen receptor modulator (SERM) to stimulate follicle growth. Clomiphene citrate treatment involves monitoring follicular growth, endometrial thickness, and progesterone levels. The starting dose depends on body weight and cycle monitoring is needed to properly time human chorionic gonadotropin injection and assess treatment response. Increasing the number of mature follicles, improving endometrial quality, and using intrauterine insemination can boost pregnancy rates when using clomiphene citrate for ovulation induction.

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3. Two ideas of ovarian stimulation
N.B: The main endogenous
hormone modulates
endogenous gonadotropins
secretion is Estrogen
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4. As estrogen is the main hormone in
regulating production of endogenous
gonadotropins
SO IT IS A TARGET HORMONE
Estrogen Receptor Modulator
SERM
Clomphine
Citerate
Tamoxifen
Aromatase Enzyme inhibition
Letrozole

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6. Clomiphene citerate
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8. Non-steroidal triphenylethylene derivative
Cis / Trans isomerism ( same number of atoms but
different orientation
Chemical structure & Pharmacokinetics:
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9. EnclomipheneZuclomiphene
More potent antiestrogenic isomerLess potent antiestrogenic action
(good?)
The main role in ovarian
stimulation
Minimal role in ovarian stimulation
½ life few daysDetected in the circulation for
about one month after last day of
administration
62% of clomiphene moleculeOnly 38% of clomiphene molecule
Hepatic elimination: avoided in cases of liver impairment
Retained in body fat so variable in half life and elimination
& dose must be adjusted according to BMI
Clomid used Cycle –ON
/Cycle-off
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Early optimal start may antiestrogenic
effect

10. Strong anti estrogen
+
Weak estrogenic activity
Competitive antagonist=
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11. WhereCCacts?
Outside CNS
antiestrogenic effect
of CC is Hostile
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13. Due to its site of action, the total daily
dose of clomiphene must be taken at
one time to optimize entry into the
hypothalamic and central nervous
system receptor sites
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14. Hostile actions of CC is due to
antagonism of E receptors in
the uterus
Poor cervical mucus quality
or quantity and fewer than
five motile sperm was found
in 39 of 100 patients
referred for gonadotropin
ovulation induction and/or
IUI because of failure to
become pregnant after 3- 8
clomiphene cycles (Dickey
2006).
Reduced endometrial
thickness
See later

15. What antiestrogenic
effect forces you to
stop CC
immediately?
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Scotoma

17. Initial evaluation & prerequisites before
induction
TVS scanning
Hormonal
profile

18. Critical US values for
ovulation induction

19. Endometrial changes during ovulation
induction
• When clomiphene citrate (CC) is used for ovulation induction,
endometrial thickness is often decreased compared with
spontaneous cycles during and immediately following the days
CC is taken, because of its antiestrogen effect
• During the late proliferative phase, endometrial thickness
increases at a faster rate in CC cycles than in spontaneous
cycles as it escapes from the antiestrogen, and the effect of
increased estrogen due to multiple follicle growth becomes
manifest.
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20. Double endometrial thickness (mm) in spontaneous (○) and clomiphene citrate (●)
cycles (mean + SEM). LH 0 = day of onset of luteinizing hormone surge. *P < 0.05. From
Randall and Templeton (1991) [7].
Reproduced with permission of the authors and the publisher, the American Society
for Reproductive Medicine (The American Fertility Society).
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21. How to measure the endometrial thickness
Thickness measured in an anterior–posterior view at the widest point from outside to
outside in an anterior-posterior view at the widest point (O–O).
The pattern is triple-line. 3‫شعبان‬1436

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23. 1. Endometrial pattern
• A triple-line pattern on the day of hCG administration has been
reported by some authors to be necessary for implantation in
controlled ovarian hyperstimulation (COH) cycles, where hMG or
FSH is administered,.
• However, Dickey et al. found no difference in initial pregnancy
rate between a triple-line pattern (10.9%) and intermediate
pattern (10.2%) in CC and COH cycles for ovulation induction
before intrauterine insemination, but noted a difference in
continuing pregnancy rates of 9.4% for the triple-line pattern
and 7.3% for the intermediate pattern .
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24. 2. Endometrial thickness
Decreased endometrial thickness is linked to failure to conceive and
biochemical pregnancy in CC, hMG, and spontaneous
cycles[13,14,15].
In a study of endometrial thickness on the day of hCG administration
for timed intrauterine insemination (IUI), optimal pregnancy and birth
(continuing pregnancy) rates occurred only when endometrial
thickness was 9mm or greater on the day of hCG administration
(Table 12.1).
More importantly, no pregnancies occurred when endometrial
thickness was less than 6mm in spontaneous, CC, or hMG IUI cycles
[13,14].
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25. Endometrial thickness according to ovulation regimen:
percent cycles; figures in parentheses are number of cycles
Endometrial thickness vs. outcome in ovulation induction
intrauterine insemination cycles

26. Ovarian cyst before ovulation induction
• Ovarian cysts larger than 4 cm should be assessed
by M-B rules according to IOTA trial 2010.
• Smaller cysts without cancer characteristics either
followed until they resolve or start your induction
agent.
• COCs has no role in treatment ovarian cyst but
may have a role in prevention other cysts
formation.
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27. Dealing with problems
detected by US
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Ovarian
cyst
Thick
endometrium

28. Hormonal profile
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Baseline Estradiol
CC will be ineffective if E ˂ 45-60 pg/ml ( Disturbed axis)
prolactin˃25 mIu/ml
Indicates ttt of hyperprolactinemia
DHEAS if ˃180 μg/dl indicates adrenal hyperplasia
Fasting insulin
In cases of insulinresistance associated with PCOs
TSH levels 4.5 mIU/mL or
higher are diagnostic of subclinicalhypothyroidism.

29. Insulin resistance in PCO cases
• Fasting insulin levels greater than 20 lU/mL
• Two-hour glucose/insulin response to a 75 g glucose load
 Two-hour insulin level of 100–150 lU/mL indicates
probable IR, 150–300 lU/mL is diagnostic for IR, and
greater than 300 lU/mL indicates severe IR.
 Two-hour glucose of 140–199 mg/dL indicates impaired
glucose tolerance; 200 mg/dL indicates noninsulin-
dependent diabetes (type II diabetes).
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30. To summarize, the initial Prerequisites
Regular
menses
TSH
Day 21 P
Androgen
excess
DHEAS/17OH P
Glucose/Insulin
FSH/LH/E
Amenorrhea
FSH/E
PRL
hCG
Irregular
menses
TSH
FSH/LH/E
Glucose/insulin
Serum FSH ˂ 25 mIu/ml
Endometrial thickness ˂ 6 mm
No ovarian cyst ˃ 3 cm
serum E levels ˃ menopausal (20 pg/mL)

31. Teratogenic ( Group X)
Extended action 8-21 days
( stored in body fat cells, depend on isomer)
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32. Administration
• Starting Day:
☑ 2nd -7th day for 5 days
 Not effective if started too early i.e.: serum E ˂45-60 pg/ml
 Starting day is affected by length of menstrual cycle ???
 Better results of CC induction are obtained with early optimal start as early start result in
early disappearance of hostile antiestrogenic effect before luteal phase
• Starting Dose:
☑ Depends on BMI (How??) or P level
Luteal phase insufficiency
needs higher starting dose
Follicle
6mm or
greater
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Relationship of Clomiphene Dose to Weight at Conception

34. Simply, Starting dose in relation to
body wt is:
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TamoxifenClomipheneWeight
20 mg25 mg
40 mg50 mg
60 mg100 mg

35. Monitoring of CC induction cycles
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36. Follicular monitoring
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Increase in diameter at a rate of 1mm per day until they
reach 10 mm, then at a rate of 2mm per day until
ovulation (Steinkampf,2008)
The highest pregnancy rates occur when there are four
follicles 15 mm or larger. When HCG is used to trigger
ovulation, highest pregnancy rates are achieved when
the lead follicle is 16 mm.
All follicles 12 mm or larger (vs. >10mmin
gonadotropin cycles) may ovulate and contribute to a
multiple pregnancy (Dickey et al., 2001).

37. Endometrial thickness monitoring
Preovulatory thickness should be ˃6 mm and better
pregnancy rate was found with endometrial
thickness 9 mm
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If 5 days post induction…there is thin endometrium:
Postpone hCG administration
Use Estrogen 4 times/day????
In subsequent cycles use low dose CC or switch to
Tamoxifen

38. Postovulatory Progesterone
• measured five to seven days after ovulation, to
coincide with the day of embryo implantation.
• supplementation should be considered in the
current cycle and the dose of clomiphene should be
increased as 50-mg increments until progesterone
levels are 2,000 ng/dL (20 pg/mL) or higher in
subsequent cycles.
Value:
confirmovulation
determine if the dose of clomiphene is sufficient.

39. Methods to Increase Pregnancy Rates in
Clomiphene Cycles
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1.Increase number of follicles
2.Improve endometrial and
cervical mucous quality
3.IUI

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Iniections SequentialOral

41. Thanks
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