3.hiferiinduksi ovulasi,nusra

8/2/2019 3.HIFERIinduksi ovulasI,nusra

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Nusratuddin Abdullah

DIVISION OF ENDOCRINOLOGY REPRODUCTION & FERTILITY

DEP. OF OBSTETRIC & GYNECOLOGY,MEDICAL FACULTY - HASANUDDIN UNIVERSITY.


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ESHRE Capri workshop 2000

The Basic Routine Infertility Investigation

Tests which have an establishedcorrelation with pregnancy are:

1- Semen analysis

2-Tubal patency by HSG or laparoscopy

3- Diagnosis of ovulation

National Guideline Clearinghouse 2000

RCOG Guidelines : Grade B Recommendation 1999


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Clomiphene Citrate

Aromatase Inhibitor (Anastrozole,Letrozole) Insulin Sensitizing Agent (Metformin)

Bromocriptin

Ovarian Drilling


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Ovarian stimulation- different approaches -

Anovulation

Single dominant

follicle development

Normal cycle

Multiple dominantfollicle development

OvulationInduction

Ovarian(hyper)stimulation

Starting point

Desired end-point

IUI/Stimulation

IVF/ICSI


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Follicular Growth

Gonadotropin independent e) Gonadotropindependent


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Physiological key pointNormally: A cohort of primordial follicles

Continuously initiating folliculargrowth (Independent of Gn stim. =intrinsic mechanism)

Preantral stage

Need FSH in appropriate level

Pre- ovulatory stage E + FSH FSH

receptor content

Dominant follicle E FSH atresia ofless developed foll.s

Ov. stim

Disturb mechanism

Many follicles


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Clomiphene Citrate


Bromocriptin

Ovarian Drilling


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It acts as a selective estrogen receptor

modulator, similar to tamoxifen and

raloxifene.

All the three drugs are competitive

inhibitors of estrogen binding to estrogen

receptors and have mixed agonist and

antagonist activity depending upon thetarget tissue.

PHARMACOLOGY


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Clomiphene action


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PHARMACOLOGY

Binds to estrogen receptors in

hypothalamus


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Estrogen negative feedback is inhibited

Clomiphene Citrate blocks estrogen receptors inhypothalamus

Hypothalamus thinks there is an estrogendeficiency, more FSH and LH secreted from Anterior

Pituitary in response to GnRH

Increase in FSH causes increased follicle

development

Increased circulatingestrogen

Hypothalamus senses this, and there is positivefeedback on the surge center

LH Surge

Ovulation Day 14

Days 2-7


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The commercially available form of

clomiphene is the dihydrogen citrate

salt(clomiphene citrate). It contains two stereoisomers:

zu-clomiphene (38 %) cis -isomer

en-clomiphene (62 %) trans-isomer

PHARMACOLOGY


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En-clomiphene is cleared rapidly,while zu-clomiphene has a longhalf-life.

The two clomiphene isomers havemixed estrogenic and antiestrogeniceffects that vary among species.

Zu-clomiphene appears to havegreater estrogenic activity thanen-clomiphene.

PHARMACOLOGY


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14C-labeled clomiphene citrateis absorbed by the gastrointestinaltract.

50% of the oral dose is excreted afterfive days, but radioactivity fromlabeled clomiphene appears in thefeces up to six weeksafter administration.

PHARMACOLOGY


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MECHANISMS OF ACTION

Clomiphene exerts its major

effects on the:1. Hypothalamus

2.Pituitary

3. Ovary and uterus.


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Hypothalamus and pituitary

Most evidence suggests that the

primary site of clomiphene

action is the hypothalamus,binding to estrogen receptors

blocking the negative

feedback effect of circulating

endogenous estrogen.


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Clomiphene treatment result in

Elevated plasma concentrations of :

1. Follicle stimulating hormone(FSH)

2. Luteinizing hormone(LH).



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When clomiphene is administered to

normally cycling women, LH pulse

frequency(but not amplitude)increases, suggesting an increase in

hypothalamic gonadotropin-releasing

hormone (GnRH) pulse frequency .



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In women with polycystic ovary

syndrome, (who have a high frequency

pattern of LH pulses at baseline),

the administration of clomiphene citrate

produces an increase in LH pulse

amplitude, as well as an increase in thedaily plasma concentrations of

LH and FSH



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In vitro data suggest that

clomiphene citrate also hasa pituitary site of action

by increasing the

gonadotropin responseto GnRH .



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Ovary

The ovarian actions of

clomiphene are for the most

part secondary to the effectsofelevated FSH and LH on

ovarian follicular development.


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Clomiphene is an estrogen

agonist in the absence of

estrogen, thereby enhancingFSH stimulation ofLH receptors

in granulosa cells.

Ovary


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Uterus and cervix

Clomiphene acts primarily

as an antiestrogen in theuterus, cervix, and vagina.


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The low pregnancy rates observed inclomiphene-induced ovulatory cycles

may be partially explained by :

The normal increase in uterinevolume and endometrial thickening

that occurs during spontaneous

menstrual cycles is largely absentduring clomiphene-induced cycles

despite higher estrogen levels .

Uterus and cervix


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The low pregnancy rates observed in

clomiphene-induced ovulatory cycles

may be partially explained by :

Some, studies have found

abnormal luteal phase endometrial

morphology in clomiphene-induced cycles.

Clomiphene citrate directly

impairs implantation efficiency in mice .

Uterus and cervix


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Treatment strategies in these

couples are empiric.

Intrauterine insemination (IUI)either alone or in combination

with superovulation is a viable

option, keeping in mind the high

spontaneous pregnancy rates

in these patients.

Unexplained infertility


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HOW TO USE

CLOMIPHENE CITRATE


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Disorders ofpituitary, adrenal, and

thyroid origin that can cause

anovulation should be excluded priorto the initiation of therapy

As targeted treatment of these

endocrinopathies can result innormal ovulation

Pretreatment evaluation


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Initiation of therapy, duration anddosage

Clomiphene citrate therapy for ovulationinduction is typically started onthe fifth day of a cycle, following either

spontaneous or induced bleeding. However, the results of therapy,

in terms ofovulatory rates,pregnancy,or spontaneous miscarriage, arecomparable when clomiphene is begun asearly as day two .


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There are

no laboratory or clinical parametersthat predict the dose of clomiphene

necessary to achieve ovulation.

Initiation of therapy, durationand dosage


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DOSES CC

DOSES(mg)

OVULATION( % )

NOTE

50 52F.D.A Recommendation

in US100 22

150 12

High dose success in

several women

200 7

250 5

Speroff Leon (2005) ; Clinical Gynecolgic Endocrinology and Infertility, ed VIIth.

Lippincott Williams & Wilkins. Page : 1170 - 1189


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There is no benefit to increasing

the clomiphene dose in subsequent

cycles once ovulationoccurs.

The LH surge occurs from

5 to 10 days after the last dayof clomiphene administration.



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The day of ovulation is generallyconsistent in each cycle once

ovulation has been established.The couple is advised to have

intercourse every other day

for one week beginning five daysafter the last day of medication.



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When ovulation occur?

Speroff Leon (2005) ; Clinical Gynecolgic Endocrinology and Infertility, ed VII th.

Lippincott Williams & Wilkins. P : 1170 - 1189


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Monitoring ovarian stimulation

Transvaginal ultrasound scanning :. No. & size of follicles

. Pattern & thickness of endometrium

Estrogen blood level


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RESULTS OF THERAPY

In women with anovulatory infertility

(in general those with polycystic

ovary syndrome) an ovulatory rate of80 % and a pregnancy rate of 30 to

40 % can be expected .


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Clomiphene resistance was defined asfailure to ovulate during the treatment

with a total dose of 200 mg of CC for atleast four cycles function.

Mitwally, M., Kuscu, K., and Yalcinkaya. T. 1999. Reproduction 14:2700-2703.

THE MODERN USE OF CLOMIFENE CITRATE


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THE MODERN USE OF CLOMIFENE CITRATE

RCOG Fertility : Assessment and treatment for people with fertility problems. RCOG Press.London (2004)

Women with WHO Group II ovulation disorders such as polycystic ovary syndrome

who ovulate with clomifene citrate but have not become pregnant after 6 months of

treatment should be offered clomifene citrate stimulated intrauterine inseminationA


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OVULATION INDUCTION


Women with WHO Group II ovulation disorders (hypothalamic pituitary dysfunction)

such as polycystic ovary syndrome should be offered treatment with clomifene citrate

as the first line of treatment for up to 12 months because it is likely to induce

ovulation.

A

Women should be informed of the risk of multiple pregnancies associated with both

clomifene citrate and tamoxifen. BWomen with unexplained fertility problems should be informed that clomifene citrate

treatment increases the chance of pregnacy, but that this needs to be balanced by the

possible risks of treatment, especially multiple pregnancyA

Women undergoing treatment with clomifene citrate should be offered ultrasound

monitoring during at least the first cycle of treatment to ensure that they receive a

dose that minimizes the risk of multiple pregnancy.GPP


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SIDE EFFECTS Ovarian hyperstition, ranging from mild, with enlarged

ovaries and abdominal discomfort; to moderate,additionally causing nausea, vomiting, or shortness ofbreath; to severe and life-threatening.

Hot flashes.

Irritability. Nausea, abdominal pain.

Headaches.

Thick cervical mucus, which sperm cannot travel

through. This can be reversed with medication orbypassed with intrauterine insemination.

Breast tenderness.

Blurred vision.

Hair loss (very rare).


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The mechanism may be related to1. Antiestrogenic effects of clomiphene citrate

on the endometrium or

2. Inhibition of steroidogenesis in granulosaand lutein cells.

Increasing the dose of clomiphene doesnot correct the luteal phase defect.

However, preovulatory hCG and/orsupplemental progesteronemay prevent the problem.

Luteal phase defect


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If ovulation does not occur: Increase Clomiphene dose

Increase duration of treatment

Add other medications

Switch to another drug

Alternative Solutions


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Ovulation induction In

WHO 2- classic treatment algorithm

CC FSH IVF

Resistant

Failure


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Ovulation induction- new treatment algorithm ?? -

CC

resistant

Metformin

+/- CC

FSH

IVF

LOD

CC

failure

Caloric Restriction / Life Style Changes


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Clomiphene Citrate


Bromocriptin

Ovarian Drilling


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Steroid Hormone Biosynthesis

O

H

O

O

OH

androstenedione

17 -HSD

testosterone

aromataseHO

OH

estradiol

+H2O

+HCOOH


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Anti estrogenic effect


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Aromatase Inhibitors

AROMATASE INHIBITOR:


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AROMATASE INHIBITOR:Anastrozole & Letrozole

- Anastrazole, Arimidex & Letrozole,

Femara- Inhibit up to 97-99 % of E2 undetected

- 100 % bioavaibility with short half life

- excreted mainly through liver

- Side effects: mild GIT, asthenia, hotflushes, headache, backache.

Anastrozole

Letrozole

Use of an aromatase inhibitor for induction of


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Letrozole

Bedaiwy, JCEM 2007, Fisher, FertSter 2002, Tulandi, FertSter 2006

Use of an aromatase inhibitor for induction ofovulation in patients with an inadequate responseto clomiphene citrateMitwailly and Casper, Fert Ster, 2001

Transient inhibition of aromatase activity inthe early follicular phase of normal cycle:

stimulation of ovarian folliculogenesissimilar as for clomiphene citrate

significantly lower number of dominantfollicular growth in FSH supported cycles


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BENEFITS

risk of OHSS

Reduce E2

Implantation rate

required Gonadotrophin

risk of premature LH surge

M h i f ti


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Mechanism of action

CENTRALHYPOTHESIS


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PERIPHERAL HYPOTHESIS

Local Action within the ovarium

Aromatase inhibition

Androgen

Follicle sensitivity to FSH

Estradiol

IGF-1Paracrine

other factors

+ FSH

Folliculogenesis

Karael et al, 2005


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Dosage of 5 mg for 5 days

considered to be the most effective

D 3-7, was considered safe, due to

rapid clearance of the drug.

5 days, was taken to mimic CCduration therapy of 5 days

Initiation of therapy, duration anddosage


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Clomiphene Citrate

Aromatase Inhibitor (Anastrozole,Letrozole)

Insulin Sensitizing Agent (Metformin)

Bromocriptin

Ovarian Drilling


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Infertility in PCOS

Obese anovulatory women

with polycystic ovary

syndrome (PCOS) andhyperinsulinemia are

sometimes unresponsiveto clomiphene treatment.


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Reducing insulin secretion

with an insulin sensitizing agent such

as metformin may :

1. Lower ovarian androgen secretion,

2. Increase the rate of spontaneous

ovulation, and3. Improve the ovarian response to

clomiphene.

Metformin

MECHANISM OF METFORMIN


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Zhou, G. et al. J. Clin. Invest. 2001;108:1167-117

Metformin

Phosphorylation / activationof AMPK

SREBP-1 expressionSREBP-1 activity

Hepatic gene expression :FAS, L-PK, S14

Hepatic FA, VLDL synthesis( hepatic FA oxidation) Hepatic glucose

production

MuscleGlucose transport

hepatic steatosis liver insulin sensitivity

plasma glucose plasma triglyceridesMetformin doesnt stimulate insulin production or make hipoglikemi (ASRM 2006)

CLOMIFEN CITRATE + M E T F O R M I N


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CLOMIFEN CITRATE + M E T F O R M I N

Fertility & Sterility . 2002 ; Vol. 77 ; 209 - 215

Check Screening Labs

Initiate Metformin and

Titrate dose to 1000 mgb.i.d. for 2 6 months

Ovulation ? Yes

No

Initiate clomiphene and titrateUp to 150 mg / dose

Ovulation

YesNo

Consider alternate treatmentMetformin)+(e.g. FSH

Continue metforminOr initiate metformin as above for 5 weeks

And start clomiphene 50 mgwith titration to 150 mg

Ovulation ? Yes

No

If predictable ovulationoccurs,Continue current regimen.If conception occurs, stop alltherapies

Continue clomipheneFor total of 6 cycles

L NEJM 2007


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Legro, NEJM 2007

RCT CC Metf CC/Metf p

Number of cases 209 208 209

Live birth rate 22% 7% 27% 0,001

Multiple Rate 6% 0% 3% 0,03

Conception inOvulators 22% 40% 46% 0,001

treatmentfirst lineCC beats Metformin in


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Insulin Sensitizing Agent (ISA)


Anovulatory women with polycystic ovary syndrome who have not responded toclomifene citrate and who have a body mass index of more than 25 should be offered

metformin combined with clomifene citrate because this increases ovulation and

pregnancy rates

A

Women prescribing metformin should be informed of the side effects associated with

its use (such as nausea, vomiting and other gastrointestinal disturbances). GPP


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Clomiphene Citrate



Bromocriptin

Ovarian Drilling


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Bromocriptine

Bromocriptine is indicated for ovulationinduction in women with galactorrhea orhyperprolactinemia .

It has also been tried in women withnormal serum prolactin and

no galactorrhea who have failedclomiphene therapy.

Hyperprolactinaemia


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Hyperprolactinaemia

Dopamine agonists are effective

treatment for women with

anovulation due to

hyperprolactinaemia

RCOG Guidelines : Grade A Recommendation


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Clomiphene Citrate



Bromocriptin

Ovarian Drilling


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Definition

Ovarian drilling :is a surgical approach

of PCOS to restore ovulation by

creating multiple perforations of

ovarian surface & stroma (inner area

of the ovary)

This procedure performs through :

Laparoscopy (Laparoscopy ovariandrilling/LOD)


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Mode of action of LOD

Several potential mechanism :

unclearThe mechanism of action of LOD still

Reduction of inhibin following LOD followedby increasing FSH secretion recruitment of a

new cohort follicles

Restoration of normal production of the putative

gonodotropin surge after laparoscopic ovarianelectrocautery


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Homburg R ;

for LODRole of Four

- 4 points of punctures

- 4 mm for depth of punctures

- 4 seconds for each puncture

- 40 watt, energy of electrocauterization (bipolar or unipolar)

Hum Rep,2003

Increased

Sensitivity


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Preoperative serum LH level

Maybe a good predictorof LOD efficacy

respond to LOD)IU/L8>(


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OVARIAN DRILLING

Women with polycystic ovary syndrome who have not responded to clomifene citrate

should be offered laparoscopic ovarian drilling because it is as effective as

gonadotrophin treatment and is not associated with an increased risk of multiple

pregnancy

A



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Clomiphene is the first line therapy foranovulation WHO type 2

If ovulation does not occur:

Increase Clomiphene dose (max 200mgs) Increase duration of treatment (8-10 days)

Add other medications (Metformin, LOD)

Switch to another drug (aromataseinhibitors)

Summary


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3.hiferiinduksi ovulasi,nusra

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