Dr. Mohamed

8/6/2019 Dr. Mohamed

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TREATMENT & PREVENTION OFTREATMENT & PREVENTION OF

OVARIAN HYPERSTIMULATIONOVARIAN HYPERSTIMULATIONSYNDROME (OHSS) USING ASYNDROME (OHSS) USING A

DOPAMINE AGONISTDOPAMINE AGONISTCABERGOLINE (DOSTINEXCABERGOLINE (DOSTINEX))

Prof. Dr. Mohamed S. ElmahaishiProf. Dr. Mohamed S. Elmahaishi


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Ovarian HyperstimulationOvarian HyperstimulationSyndromeSyndrome


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Ovarian hyperstimulation syndrome(OHSS) can occur when drugs areused to stimulate the ovaries toproduce the eggs needed forfertilization in A.R.T ( IVF )treatment.


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Three grades of OHSS can be diagnosedclinically and sonographicaly:

1- Mild OHSS : is associated with mildabdominal discomfort, and the ovariesare usually less than 5 cm in diameter onsonographic examination.

2- moderate OHSS: the ovaries measurebetween 5 and 10 cm& associated withmore abdominal pain


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3- severe OHSS: the ovaries are greater than 10cm in diameter & characterized by thepresence of free intraperitoneal fluid (ascites)

due to increased vascular permeability.

Pleural effusions, hypotension, and oliguria havealso been described.

The patient also may have fluid and electrolytedisturbances and is at increased risk fortorsion of the enlarged ovaries& increased riskfor thrompotic problems.

Severe OHSS occurs in fewer than 2% ofpatients.

this can be life-threatening.


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Although ovarian hyperstimulationsyndrome has been known for

many years, until now it has beentreated empirically and theunderlying causes have beenpoorly understood.


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The existence of a vasoactive

molecule released in response tohCG & high level of E2 is believedto be the main feature associatedwith the increased vascularpermeability that occurs withdevelopment of OHSS, and vascularendothelial growth factor (VEGF) is

the main candidate as the hCGmediator (Gomez et al., Endocrinology. 2002)


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dopamine has been shown to cause

renal vasodilatation and diuresis.In one study, docarpamine, an oraldopamine prodrug, wasadministered to 27 patients withtreatment-resistant OHSS .

Diuresis was increased in somewomen, and ascites was

decreased.(Tsunoda et al., Gynecol Endocrinol. 2003)


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Dopamine agonists are primarily used for theDopamine agonists are primarily used for thetreatment of Parkinson's disease due to theirtreatment of Parkinson's disease due to theirneuroprotective effects on dopaminergicneuroprotective effects on dopaminergic

neurons.neurons.

Dopamine agonists prescribed to reduce TheDopamine agonists prescribed to reduce Thelevel of prolactin (hyperprolactinaemia).level of prolactin (hyperprolactinaemia).

Abnormally high prolactin may cause menstrualAbnormally high prolactin may cause menstrualchanges in women, and impotence in men.changes in women, and impotence in men.

can also be prescribed to prevent the productioncan also be prescribed to prevent the productionof milk inof milk in

women after birth, if breastwomen after birth, if breast--feeding is to befeeding is to beprevented for medical reasons.prevented for medical reasons.


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A "dopamine agonist" refers to anyA "dopamine agonist" refers to any

compound which competes withcompound which competes withdopamine for binding to thedopamine for binding to thedopamine Ddopamine D22 receptor.receptor.

dopamine agonists include, but aredopamine agonists include, but arenot limited to, (Dostinexnot limited to, (Dostinex) wich is) wich isa longa long--acting ergot derivativeacting ergot derivativeagonist with a high affinity for Dagonist with a high affinity for D22receptorsreceptors


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Side effectsSide effects 00ffDostinex:Dostinex:

Hypotention.Hypotention.

dizziness, faintingdizziness, faintingheadacheheadache

nausea or vomitingnausea or vomiting

unusual sleepinessunusual sleepiness

constipationconstipation

nosebleednosebleed

weakness or tirednessweakness or tiredness

temporary impairment of visiontemporary impairment of visionbreast painbreast pain

hot flusheshot flushes

changes in behaviour such as aggression,changes in behaviour such as aggression,

depression, increased sex drivedepression, increased sex drive


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PreventionofOHSSPreventionofOHSS

For prevention of OHSS in patients undergoingFor prevention of OHSS in patients undergoingfertility treatment or IVF involving thefertility treatment or IVF involving theadministration of gonadotrophic hormones, itadministration of gonadotrophic hormones, itis expected that administration of theis expected that administration of thedopamine agonist cabergoline will prevent andopamine agonist cabergoline will prevent an

increase in vascular permeability.increase in vascular permeability.

Without being limited to a particularWithout being limited to a particularmechanism, it is expected that this will occurmechanism, it is expected that this will occur

as a result of cabergoline binding toas a result of cabergoline binding todopamine Ddopamine D22 receptors, resulting inreceptors, resulting ininternalization of VEGFinternalization of VEGF--RR22, thereby, therebypreventing binding of VEGFpreventing binding of VEGF--A to VEGFA to VEGF--RR22and phosphorylation of VEGFand phosphorylation of VEGF--RR22..


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Claudio Alvarez, from the InstitutoClaudio Alvarez, from the InstitutoValenciano de Infertilidad,Valenciano de Infertilidad,

Valencia, Spain, said that hisValencia, Spain, said that histeam's work, using the dopamineteam's work, using the dopamineagonist Cabergoline ( Dostinex),agonist Cabergoline ( Dostinex),

was the first successful attempt towas the first successful attempt toprevent this disorder.prevent this disorder.


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Animal models had shown that increased vascularAnimal models had shown that increased vascularpermeability, a factor in ovarianpermeability, a factor in ovarianhyperstimulation syndrome, was associated with anhyperstimulation syndrome, was associated with an

increased expression in the ovary of vascularincreased expression in the ovary of vascularendothelial growth factor ( VEGF), responsible forendothelial growth factor ( VEGF), responsible forthe growth of blood vessels. The binding of VEGF tothe growth of blood vessels. The binding of VEGF toits receptor VEGFRits receptor VEGFR22 increases vascular permeability.increases vascular permeability.

" We knew that dopamine and its agonists also reverse" We knew that dopamine and its agonists also reverseincreased vascular permeability in hyperstimulatedincreased vascular permeability in hyperstimulatedanimals", said Alvarez, "animals", said Alvarez, "

so we decided to see whether it could prevent ovarianso we decided to see whether it could prevent ovarianhyperstimulation syndrome in women undergoinghyperstimulation syndrome in women undergoingovarian stimulation for ART."ovarian stimulation for ART."


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for prevention, cabergoline (Dostinexfor prevention, cabergoline (Dostinex) is administered) is administeredduring controlled ovarian stimulation (withduring controlled ovarian stimulation (withgonadotropins or other ovarian stimulating agents)gonadotropins or other ovarian stimulating agents)prior to triggering final maturation/ovulation withprior to triggering final maturation/ovulation withe.g., hCG. Preferably, administration is initiatede.g., hCG. Preferably, administration is initiatedduring the last week of stimulation. Administration isduring the last week of stimulation. Administration iscontinued for about one to three weeks after hCGcontinued for about one to three weeks after hCGstimulation.stimulation.

For treatment of OHSS, administration of cabergoline isFor treatment of OHSS, administration of cabergoline isinitiated once a patient has been diagnosed withinitiated once a patient has been diagnosed withmoderate to severe OHSS(when signs and symptomsmoderate to severe OHSS(when signs and symptoms

of OHSS first appear) . at a dose of aboutof OHSS first appear) . at a dose of about 00..0505 toto 11..00mg/day from aboutmg/day from about 11 to aboutto about 2828 days, preferably fromdays, preferably from

aboutabout 77 to aboutto about 1414 days, or until symptoms abate.days, or until symptoms abate.

(( Source: European Society for Human Reproduction and Embryology,Source: European Society for Human Reproduction and Embryology, 20062006).).


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" We found that Cabergoline reduced" We found that Cabergoline reducedhemoconcentration, ascites and thehemoconcentration, ascites and theincidence of moderate to severeincidence of moderate to severeovarian hyperstimulation syndrome inovarian hyperstimulation syndrome inwomen at risk," said Alvarezwomen at risk," said Alvarez


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At our clinic (Misurata IVF center &lamis IVF center)At our clinic (Misurata IVF center &lamis IVF center)We start to use use destinox at januaryWe start to use use destinox at january 20082008..

we use destinox forwe use destinox for 2626 cases;cases;-- 44 pt as therapeutic measure ; they present with OHSS &pt as therapeutic measure ; they present with OHSS &

pregnancy.pregnancy.

one of them present with twins pregnancy &two withone of them present with twins pregnancy &two withtriplets pregnancy &one withtriplets pregnancy &one with 55 fetuses.fetuses.

In this group of pt we used dostinex one tabIn this group of pt we used dostinex one tab 00..55mg /daymg /dayforfor 1010 days.days.

Fetal reduction to two fetuses done for all.Fetal reduction to two fetuses done for all.

One ended by abortion atOne ended by abortion at 2020 wks .wks .

One of them delivered by c/s healthy boy & girle.One of them delivered by c/s healthy boy & girle.One now atOne now at 3636wkswksOne atOne at 3030wks& both twins pregnancy at good generalwks& both twins pregnancy at good general

conditioncondition..


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We Use destinox as prophylactic ofWe Use destinox as prophylactic of00HSS forHSS for 2222 casescases

The criteria for using destinox inThe criteria for using destinox inthis group were:this group were:

11. No of egges picked up for ICSI =. No of egges picked up for ICSI =2020 eggs or more.eggs or more.

22. Ovarian size from. Ovarian size from1010 --1515cmcmascites.ascites.

33. E. E22 level at day of ovum pick uplevel at day of ovum pick up>>20002000pg/mlpg/ml


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The dose of Destinox wasThe dose of Destinox was 00..55mg tab oncemg tab oncedaily fordaily for 55days started at day of pickdays started at day of pick

up.up.

E.T were done in blastocyst stage.E.T were done in blastocyst stage.

all pts were seen again at two wks postall pts were seen again at two wks postE.T for serum BhcG level & transvaginalE.T for serum BhcG level & transvaginaluss.uss.

In all pt there were no signs or symptomsIn all pt there were no signs or symptoms

ofof 00HSS.HSS.

Ten pt out ofTen pt out of 2222 pt were pregnantpt were pregnant ..


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Since using destinox we have noSince using destinox we have noadmitted cases with OHSS.admitted cases with OHSS.

So now we are using it as prophylacticSo now we are using it as prophylacticmeasure for OHSS.measure for OHSS.


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THANKSTHANKS

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