Ovarian stimulation oral agents

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

Apr 15, 2023

SERMAHMAD SABER

Apr 15, 2023

Clomiphene citerate

AHMAD SABER


Clomiphene was initially used as

estrogen prepared for contraception


Non-steroidal triphenylethylene derivativeCis / Trans isomerism ( same number of atoms but different orientation

Chemical structure & Pharmacokinetics:

Apr 15, 2023

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


Strong anti estrogen

+ Weak estrogenic activity

Competitive antagonist

=


Where

CC acts?

Outside CNS antiestrogenic effect of

CC is Hostile


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


What antiestrogenic

effect forces you to stop CC immediately?


Scotoma

Initial evaluation & prerequisites before induction

TVS scanningHormonal

profile

Critical US values for ovulation

induction


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.


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).

Apr 15, 2023

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.


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 .


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


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.


Dealing with problems detected by US

Ovarian cyst

Thick endometrium


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.

Apr 15, 2023

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)


Teratogenic ( Group X)

Extended action 8-21 days ( stored in body fat cells, depend on isomer)

AHMAD SABER

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

Apr 15, 2023

ahmad

WeightClomiphene is not sequestered in fat cells as occurs for naturalsteroids, but because blood volume constitutes 15 percentof total body weight, serum levels of clomiphene are related tobody weight. An analysis of the clomiphene dose taken duringthe cycle of conception illustrates the relationship betweenweight and effective dose (Table 23.4; Dickey et al., 1997).Sixty-six percent of women who weighed less than 100 lb (45kg) became pregnant on 50 mg per day, compared to 24 percentof women who weighed 198 lb (90 kg) or more. Doses of 100 mgor more were taken for the cycle of conception by 42 percent ofwomen weighing 100–131 lb (45–59 kg), 54 percent of womenweighing 132–164 lb (60–74 kg), and 64 percent of womenweighing 165–197 lb (75–89 kg). There was a positive relationshipbetween clomiphene dose and the number of follicles, butno relationship to multiple pregnancies or abortion. Because ofclomiphenes antiestrogen effects on endometrium thickness(Dickey et al., 1993a), and mucus, the starting dose shouldnot be greater than 50 mg for women who weigh less than132 lb (60 kg). A starting dose of 100 mg is recommended foruse in women who weigh 165 lbs (75 kg) or more, providingthat endometrial thickness and cervical mucus are monitored.


Relationship of Clomiphene Dose to Weight at Conception


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


Monitoring of CC induction cycles

PreovulatoryTVS done 5 days after last tablet

PostovulatorySerum progesterone

Apr 15, 2023

Follicular monitoring

AHMAD SABER

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).


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.


Methods to Increase Pregnancy Rates in Clomiphene Cycles

1.Increase number of follicles

2.Improve endometrial and cervical mucous quality

3.IUI


Iniections SequentialOral


Thanks

Ovarian stimulation oral agents

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