ovarian stimulation oral agents
TRANSCRIPT
Ovarian Stimulatio
n (Oral agents)
By Ahmad Saber
Apr 15, 2023
Apr 15, 2023AHMAD SABER
Two ideas of ovarian stimulation
Direct Gonadotropins
IndirectEndogenous gonadotropin
modulationOral agents
N.B: The main endogenous hormone modulates
endogenous gonadotropins secretion is Estrogen
As estrogen is the main hormone in regulating production of endogenous
gonadotropinsSO IT IS A TARGET HORMONE
Estrogen Receptor Modulator
SERMClomphine
CiterateTamoxifen
Aromatase Enzyme inhibition
Letrozole
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Clomiphene citerate
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Clomiphene was initially used as
estrogen prepared for contraception
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Non-steroidal triphenylethylene derivativeCis / Trans isomerism ( same number of atoms but different orientation
Chemical structure & Pharmacokinetics:
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Enclomiphene
Zuclomiphene
More potent antiestrogenic isomer Less potent antiestrogenic action (good?)
The main role in ovarian stimulation
Minimal role in ovarian stimulation
½life few days Detected in the circulation for about one month after last day of
administration
62% of clomiphene molecule Only 38% of clomiphene molecule
Hepatic elimination: avoided in cases of liver impairmentRetained in body fat so variable in half life and elimination & dose must be adjusted according to BMI
Clomid used Cycle –ON /Cycle-off
Early optimal start may antiestrogenic effect
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Strong anti estrogen
+ Weak estrogenic activity
Competitive antagonist
=
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Where
CC acts?
Outside CNS antiestrogenic effect of
CC is Hostile
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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
Hostile actions of CC is due to antagonism of E
receptors in the uterusPoor 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 thicknessSee later
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What antiestrogenic
effect forces you to stop CC immediately?
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Scotoma
Initial evaluation & prerequisites before induction
TVS scanningHormonal
profile
Critical US values for ovulation
induction
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Endometrial changes during ovulationinduction
• 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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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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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.
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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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2. Endometrial thicknessDecreased 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].
Endometrial thickness according to ovulation regimen:percent cycles; figures in parentheses are number of cycles
Endometrial thickness vs. outcome in ovulation inductionintrauterine insemination cycles
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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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Dealing with problems detected by US
Ovarian cyst
Thick endometrium
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Hormonal profileBaseline 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 insulin resistance associated with PCOs
TSH levels 4.5 mIU/mL or
higher are diagnostic of subclinical
hypothyroidism.
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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).
To summarize, the initial Prerequisites
Regular
mensesTSH
Day 21 P
Androgen
excessDHEAS/17OH PGlucose/Insulin
FSH/LH/E
AmenorrheaFSH/E
PRLhCG
Irregular menses
TSHFSH/LH/E
Glucose/insulin
Serum FSH ˂ 25 mIu/mlEndometrial thickness ˂ 6 mm
No ovarian cyst ˃ 3 cmserum E levels ˃ menopausal (20 pg/mL)
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Teratogenic ( Group X)
Extended action 8-21 days ( stored in body fat cells, depend on isomer)
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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
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Simply, Starting dose in relation to body wt is :
Tamoxifen Clomiphene Weight
20 mg 25 mg ˂45 kgs
40 mg 50 mg 45-75 kgs
60 mg 100 mg ˃75 kg
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Monitoring of CC induction cycles
PreovulatoryTVS done 5 days after last tablet
PostovulatorySerum progesterone
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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).
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Endometrial thickness monitoring
Preovulatory thickness should be ˃6 mm and better pregnancy rate was found with endometrial thickness 9 mm
If 5 days post induction…there is thin endometrium:Postpone hCG administrationUse Estrogen 4 times/day????In subsequent cycles use low dose CC or switch to Tamoxifen
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:
confirm ovulation
determine if the dose of clomiphene is sufficient.
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Methods to Increase Pregnancy Rates in Clomiphene Cycles
1.Increase number of follicles
2.Improve endometrial and cervical mucous quality
3.IUI
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Iniections SequentialOral
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Thanks