induction ovulation

7/27/2019 Induction Ovulation

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Infertility: 1 year of unprotectedintercourse without pregnancy

Primary infertility: no previous pregnancy has occurred

Secondary infertility: infertility + prior pregnancy, although not necessary a live

birth

Fecundability is the probability ofachieving pregnancy within a single

menstrual cycle

Fecundity is the probability ofachieving a live birth within a single cycle

Fecundability of the normal couple has 20-25%

90% of couples should conceive after 12 mo. Of unprotected intercouse


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Cause ofinfertility

1.male factor 25-40%

2.female factor 40-55%

3.both female and male factor 10%

4.unexplained infertility 10%


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Cause of female factor

1.ovulation dysfunction 30-40%

2.tubal or peritoneal factor 30-40%

3.unexplained infertility 10-15%

4.miscellaneous causes 10-15%


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Diagnosis of anovulation

:

irregular, unpredictable or infrequent menses

When anovulation is suspected but uncertain

-basal body temperature

-progesterone measurement

-urinary LH secretion


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Basal body temperature

Measured each morning, on awakening and before arising

Measured with an oral glass/mercury thermometer

Test of ovulation: based on thermogenic property of progesterone

Level of progesterone rise after ovulation so BBT increase

BBT in follicular phase 97.0-98.0 F then higher in luteal phase (0.4-0.8F) andfall again to baseline just before or onset of mense

Call Biphasic pattern: ovulation

Thermogenic shift when progesterone > 5 ng/ml

Most fertile interval is 2 day after thermogenic shift


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progesterone measurement

Levels generally remain below 1

ng/ml during follicular phaseRise slightly on the day of LH

surge 1-2 ng/ml

Peak 7-8 day after ovulation then

decline before mense

Level > 3 ng/ml ovulation


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urinary LH secretion

LH has short half life and rapid clear in urine

Ovulation prediction kits or LH kits detect mid cycle LH surge in urine

Test positive in single day, occasionally on 2 consecutive days

Test must be done on daily, begin 2 or 3 days before surge

Logically, first morning void : ideal specimen

LH surge often begin in the early morning and are not detected in urine until several hr. later


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urinary LH secretion cont.

Ovulation generally follow within 14-26 hr. after detection of urine LH

surge and almost always within 48 hr.

Interval of greatest fertility include the day of LH surge detection and

following 2 days

The day after the first positive test is the onebest day for times

intercourse and artificial insemination


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Evaluation before induction of ovulation

anovulation

thyroid disease, hyperprolactinemia, adrenaldisease, pituitary or ovarian tumors, extremes of weight loss or

exercise, polycystic ovary syndrome and obesity

chronic anovulation risk endometrialhyperplasia and neoplasm endometrial sampling irregular mense


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Classification of ovulation disorders

Group1:hypothalamic-pituitary failure:hypothalamic

amenorrhea stress, weight loss, exercise,anorexia nervosa and its variants, Kallmann syndrome and

isolated gonadotropin deficiency hypothalamic orpituitary mass lesion

Labs: low FSH and estrogen level normal prolactinconcentration


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Group2:hypothalamic pituitary dysfunction

amenorrhea or oligomenorrhea with or without associated hyperandrogenism

PCOS with anovulation

Labs:normal FSH, estrogen and prolactin concentration

Group3:ovarian failure

amenorrhea

elevated serum FSH


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Evaluation of other infertility factors

Before ovulation induction shouldscreening semen analysis

because infertility male factor20-40% coexist preliminary evaluation with HSG or transvaginal

ultrasonography when

-history of previous pelvic infection or surgery, ectopic

pregnancy, inflammatory bowel disease, pelvic pain or othersymptom of endometriosis oran abnormal physical

examination


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Evaluation of other infertility factors cont.

older women : rapidly narrowing window of opportunity

evaluate all relevant infertility factors before treatment

induction ovulation exogenous gonadotropin shouldpreliminary evaluation

recommended : preliminary HSG and transvaginal

ultrasonography when medical history or physical examination

suspected coexisting uterine or tubal infertility factors,age

over35, and when ovulation induction required with

exogenous gonadotropins


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Evaluation of other infertility factors cont.

laparoscopy when abnormal HSG or signs and symptom of

advanced pelvic disease


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Induction of ovulation

Clomiphene citrate

Exogenous gonadotropinsExogenous GnRH

Dopamine agonists


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Induction of ovulation with Clomiphene citrate

Clomiphene citrate first synthesized in 1956

approved for clinical use in United States in 1967anovulatory women who recieve clomiphene citrate :

-80% ovulation

-50% of ovulated conceived
http://images.google.co.th/imgres?imgurl=http://www.uschemist.com/pcat-gifs/products-small/clomid-bg.jpg&imgrefurl=http://www.uschemist.com/clomid-generic.html&h=240&w=230&sz=7&hl=th&start=4&tbnid=MBkty_yqDbPtyM:&tbnh=110&tbnw=105&prev=/images%3Fq%3Dclomid%26gbv%3D2%26hl%3Dth


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Pharmacology of Clomiphene

nonsteroidal triphenylethylene derivertive estrogen agonist and antagonist properties

Main act purely as an antagonist or anti-estrogen weakestrogenic action

metabolism 85%

1

2 different stereoisomers :

1.enclomiphene 2.zuclomiphene


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Mechanism of action

compete estrogen nuclear estrogen receptor

receptor receptorinterfere receptor recycling

hypothalamus: depletion estrogen receptor interpretation of estrogen level estrogen negative feedback GnRHsecretion increase pituitary gonadotropin drive ovarian

follicular development


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Indications for Clomiphene treatment

traditional drug of choice for ovulation induction

anovulatory infertile women evidence endogenous estrogen production 1. clinical oligomenorrhea, estrogen cervical mucus2.serum estradiol determination (>40pg/ml)

3.normal menstrual response to progestational challenge

hypogonadotropic hypogonadism clomiphene


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Indications for Clomiphene treatment cont.

Luteal phase deficiency:clomiphene

preovulatory follicular development Unexplained infertilityinfertility aggressive treatmentEmpiric clomiphene treatment intrauterine insemination


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Clomiphene treatment regimen

Administer orally 3-5

progestin induced mensesamenorrheic women

start dose 50 mg tablet daily 5 50mg cycle ovulation

dose 150 mg daily aggressive therapeutic alternation


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Monitoring Clomiphene treatment

evaluate anovulation

clomiphene induced ovulatory cycles anovulatory womenLH surge 5-12 16-17 transvaginal ultrasound developing follicles presumptive evidence ovulation

combined treatment with clomiphene and IUI transvaginal ultrasound : development of more than a single


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Results of Clomiphene treatment

successfully induce ovulation in approximately80% of

properly selected women

overall cycle fecundability is 15% anovulation ovulate clomiphene treatment

Cumulative pregnancy rates of70-75% can be expected

over6-9 cycles of treatment

clomiphene induce ovulation 3-6 cycles ovulate infertility investigation exclude any other infertility

factors


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Results of Clomiphene treatment cont.

luteal phase deficiency luteal phase

duration, serum progesterone concentration and cyclefecundability

Empirical clomiphene treatment has relatively little benefit,

yielding cycle fecundability 5 % and only one additional

pregnancy for every 40 cycles

Combined treatment with clomiphene and IUI achieves cycle

fecundability between 8-10% and one additional pregnancy

for every15-20 treatment cycles


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Side Effects of Clomiphene

Minor side effects are common

transient hot flushes 10%,vasomotor symptoms, moodswing common, other mild or less common side effects include

breast tenderness, pelvic pressure or pain, and nausea

Visual disturbance(blurred or double vision, scotomata, light

sensitivity) are uncommon


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Peripheral Antiestrogenic effects of Clomiphene

peripheral sites in reproductive system : endocervix,

endometrium, ovary, ovum and embryoCervical mucus : cervical mucus production Endometrial growth and development : estrogenmediated endometrial growth minor effect orpeak preovulatory endometrial thickness < 6mm tamoxifen or letrozole

Ovary and embryo: embryo ovum


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Risks of clomiphene treatment

multiple pregnancy :risk increased to 5-8 %

congenital anomalies: no substantial evidence to increases

miscarriage: no difference

ovarian hyperstimulation syndrome transient abdominal discomfort, mild nausea,vomiting, diarrhea, and abdominal distention supportive

breast and ovarian cancer: fertility drug nulliparoussubfertile women incidence of borderline serous ovariantumors but not with any invasive cancers


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Treatment options after clomiphene failure

Clomiphene failure failure to ovulate in response to

clomiphene treatmentMany clomiphene resistant anovulatory infertile women

response to alternative or combination treatment regimen


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Options include

1.longer duration of clomiphene treatment, (7-10 days VS standard 5days treatment regimen)

2.adjuvant treatment with glucocorticoids or exogenous human chorionicgonadotropin

3.preliminary suppressive therapy(oral contraception)

4.insulin sensitizing agent(metformin)

5.aromatase inhibitors(letrozole)

6.combination treatment

7.surgery ovarian wedge resection


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Extended course clomiphene treatment

>50% response standard5 day treatmentregimen(150 mg daily) ovulate after longer duration ofclomiphene treatment (7-10 days)


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Clomiphene and glucocorticoids

induce ovulation

fail to response to clomiphene alonemost efficacious in women having elevated serum

dehydroepiandrosterone sulfate (DHAS) concentration andalso effective in those with normal DHAS and unselected

populations of clomiphene resistant womenMechanism of glucocorticoid action remain unclear

combined treatment 3-6 cycles


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Clomiphene and hCG

Exogenous hCG LH surge

IUI unexplained infertilityand with coexisting male factortransvaginal ultrasound follicles maturefor ovulation hCG follicles

mature follicles induce atresia ovulationpeak preovulatory follicular diameter in successful clomiphene

induced ovulatory cycles ranges between 18-30 mm(mean25 mm)

Preovulatory follicle grows approximately 2 mm per day


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Clomiphene and hCG cont.

Combined treatment with clomiphene and IUI

insemination 1 detect LH surge ovulation generally occurs 14-26 hrs after urinaryLH surge detection

Exogenous hCGcan be useful fail to detect the LH surge

Ovulation occurs 34-46 hrs after hCG injection IUIusually performed approximate 36 hrs later


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Preliminary suppressive therapy

Anovulation dysfunctional hypothalamic

pituitary ovarian axis

long used oral contraceptive empirically to suppress the often

elevated androgen level clomiphene resistantanovulatory women

ovulation rate excess 70% andcumulative pregnancy rate over50%


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Insulin sensitizing agents

Anovulation infertile women with PCOS and hyperinsulinemia

clomiphene

5% ovulatorycycle screening for impaired glucose tolerance and diabetes

PCOS insulin resistance insulin sensitizingagent Oral hypoglycemic drug DM insulin level


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Insulin sensitizing agents cont.

metformin alone PCOS

4 metformin first line PCOS with anovulation

adjuvant therapy clomiphene resistant anovulationMetformin is commonly associated with gastrointestinal side

effects including nausea, vomiting, abdominal clamp, and

diarrhea


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Letozole

aromatase inhibitor

may be another potential option for clomiphene resistant

anovulatory women

Mechanism of action:

Blocking action of enzyme aromatase to convert testosterone

and androstenedione to estrogen

inhibit peripheral estrogen production and no direct peripheral

antiestrogen effect


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http://images.google.co.th/imgres?imgurl=http://www.genericsmed.com/images/letrozole.jpg&imgrefurl=http://www.genericsmed.com/index.php%3Fmain_page%3Dproduct_info%26products_id%3D481&h=453&w=500&sz=44&hl=th&start=1&tbnid=13FIA1gKHsLYuM:&tbnh=118&tbnw=130&prev=/images%3Fq%3Dletrozole%26gbv%3D2%26hl%3Dth


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Laparoscopic ovarian drilling

The technique involve multifocal ovarian cautery, diathermy, or laser

vaporization (approximate 10-20 sites per ovary)

aimed to decreasing intraovarian and systemic androgen concentrations

by ablating some of the hypertrophic stroma in polycystic ovaries

ovarian drilling adhesion fertility function40-90% of women have ovulated after laparoscopic ovarian drilling and

at least half of those have conceived
http://images.google.co.th/imgres?imgurl=http://www.ivf-infertility.com/images/ovarian_drilling.jpg&imgrefurl=http://www.ivf-infertility.com/infertility/treatment/ovarian11.php&h=288&w=390&sz=24&hl=th&start=1&tbnid=9bi-QsaYW8jXqM:&tbnh=91&tbnw=123&prev=/images%3Fq%3Dlaparoscopic%2Bovarian%2Bdrilling%26gbv%3D2%26hl%3Dth


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Laparoscopic ovarian drilling cont.

clomiphene resistant : ovarian drilling clomiphene and exogenous gonadotropin treatment option in clomiphene resistant anovulatory infertile

women


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Induction of ovulation with Exogenous gonadotropins

Exogenous gonadotropinhave been used for more than 40 yearsto induce ovulation in gonadotropin deficient women and those who fail

to respond to other


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Indications for exogenous gonadotropin treatment

1.hypogonadotropic hypogonadism

2.clomiphene resistant ovulation

3.unexplained infertility


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hypogonadotropic hypogonadism

drug of choice is menotropins contain both FSH and LH

LH is also required for normal steroidogenesis, luteinization,

and ovulation

insufficient luteal phase support :premenstrualspotting, grossly short luteal phase, and endogenous LH less

than 3 IU/L

luteal support: supplemental hCG(2,000-2,500IU every 3-4 days) or progesterone


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clomiphene resistant ovulation

exogenous gonadotropin is alternative choice

Clomiphene resistant anovulatory women with PCOS

Dose hypogonadotropic hypogonadismclomiphene resistant anovulatory women with polycystic ovary

syndrome generally respond to relatively low doses of

gonadotropin level

luteal phase support in PCOS


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unexplained infertility

increase cycle fecundity

superovulationdose

luteal phase support


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Exogenous gonadotropin treatment regimen

1.Step-up regimen

2.Step-down regimen

3.Sequential treatment with clomiphene and gonadotropins

4.Adjavant treatment with GnRH agonists

5.Novel gonadotropin treatment regimens


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1.Step-up regimen

Use in hypogonadotropic hypogonadism clomiphene

resistant anovulation dose 75 IU daily effective dose

4-7 evaluate serumestradiol level with or without transvaginal sonography

PCOS exogenous gonadotropin mornitor


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1.Step-up regimen cont.

Ovarian hyperstimulation

low slow treatment regimengonadotropin stimulating span 7-12

PCOS low dose longer duration metformin gonadotropin improveresponse


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2.Step-down regimen

high dose (150-225 IU daily) and decrease graduallyregimen response threshold one or more previous stimulating cycles


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3.Sequential treatment with clomiphene and gonadotropins

clomiphene resistant anovulation unexplained infertility

benefitTypical cycle involves a standard course of clomiphene

treatment (50-100 mg daily) followed by low dose FSH or

hMG (75 IU daily) beginning on the last day of clomiphene

therapy or the next day

monitor standard gonadotropin stimulated cycles


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4.Adjavant treatment with GnRH agonists

clomiphene resistant anovulation with PCOS : premature

follicular luteinization during exogenous gonadotropinstimulationhigher incidence of spontaneous miscarriage

preliminary treatment with long acting GnRH agonist before

exogenous gonadotropin stimulation : prevent premature

luteinization

riskpoor luteal function residualGnRH agonist induced LH suppression


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5.Novel gonadotropin treatment regimens

normal ovulatory cycle : preovulatory follicular development

are completed while FSH levels continue a steady declinedominant follicle highly sensitive FSH development smaller less FSH sensitivity follicle in cohort atresia

preovulatory phase : estrogen and FSH LH receptor granulosa cell dominant follicle


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5.Novel gonadotropin treatment regimens cont.

low doses of hCG or recombinant LH can selectively promote

larger follicle growth

remains quite limitedhypogonadotropic hypogonadism or PCOS : recombinant LH

treatment (225-450 IU daily) during latter stages of

follicular development can decrease the number of developingfollicles

little effect on circulatingprogesterone and testosterone

concentration and risk of causing premature luteinization or

otheradverse effect is low


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Monitoring gonadotopin therapy

To achieve ovulation but also avoid ovarian hyperstimulation

and minimize the risk for multiple pregnancyserial serum estradiol measurements and ovarian

ultrasonography


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Serum estradiol level

follicles 10 mm estrogen estradiol exponential 2 2-3 follicle maturenatural ovulatory cycle, estradiol peak 200-400 pg/ml just

before LH surgeexisting gonadotropin stimulation regimen, best results when

estradiol concentration peak500-1,500 pg/ml, pregnancy are

rare at level below 200 pg/ml


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ovarian ultrasonography

antral follicles can be identified by

cycle day 5-7dominant follicle emerges by day 8-12

grows approximately 1-3 mm per day

thereafter

most rapidly over 1-2 days

immediately preceding ovulation

follicle 20-24 mm LH surge


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exogenous gonadotropin stimulating cycles: reach

maturity at a smaller mean diameterFollicle


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Larger number of intermediate and small follicles also increase

risk for ovarian hyperstimulation syndrome

hCG risk high multiple ovulation

goal of treatment is unifollicular ovulation


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Result of exogenous gonadotropin treatment

successfully induce ovulation in >90% either hypogonadotropic hypogonadism or clomiphene

resistant anovulation

Hypogonadotropic hypogonadismCycle fecundity rate 25%, equal or greater than normal fertile women

Cumulative pregnancy rate after 6 mo. 90%

Clomiphene resistant anovulation

Cycle fecundity rate 5-15%

Cumulative pregnancy rate 30-60%

hyperandrogenic chronic anovulation have poorest prognosis


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Result of exogenous gonadotropin treatment cont.

Multiple pregnancy

spontaneous1.25%

clomiphene induce 5-8%

gonadotropin 15-30%

Normal frequency of monozygotic twin 0.3-0.4%, increase 3 fold with exogenous gonadotropin

Incidence ofspontaneous miscarriage in gonadotropin induced conception cycle is 20-25%,

moderately higher than general 15%

clomiphene and gonadotropin congenital anomalies


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Risks of exogenous gonadotropin treatment

Multiple pregnancy

Ovarian hyperstimulation syndrome


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cycle cancellation

withholding hCG 1.serum estradiol level rise above 900-1,400 pg/ml

2.ultrasonography reveals more than 4-6 follicles larger than

10-14 mm


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high order multiple pregnancy3

1.termination of entire pregnancy

2.continuing pregnancy riskpretermbirth, increase neonatal morbidity and mortality and long term

disability

3.multifetal pregnancy reduction


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Ovarian hyperstimulation syndrome

1.ovulation induction with exogenousgonadotropin

2.clomiphene induced cycle

3.spontaneous pregnancy associated with

condition characterized by supraphysiologic concentration of

hCG (multiple gestation or molar pregnancy)


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Pathophysiology of Ovarian hyperstimulation syndrome

ovary vasoactive substance vascularendothelial growth factor, element of renin-angiotensin system

and other cytokine capillary permeability fluidshift from intravascular fluid to extravascular space


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Risk factor of Ovarian hyperstimulation syndrome

young age

low body weight

PCOS

higher dose of gonadotropin

previous episodes of hyperstimulation

increase with serum estradiol level and number of developing ovarian

follicles

supplemental doses of hCG are administered after ovulation for luteal

phase support


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symptom

Mild symptom

Moderate symptom

Severe symptom


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Mild symptom

characterized by ovarian enlargement, lower abdominal

discomfort, mild nausea and vomiting, diarrhea, and abdominal

distention

oral analgesic and counselling to alert affectedwomen to sign and symptoms of progressive illness


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Modarate symptom

persistent and worsening symptom or ascites progression of illness

antiemetics and potent oral analgesics OPD careful monitoring ofdaily weights and urinary frequency, serial examination to

detect increase ascites, and laboratory evaluation of Hct., serum

Cr.


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Severe symptom

uncommom 1%severe pain, rapid weight gain, tense ascites, hemodynamic instability, respiratory

difficulty, progressive oliguria and laboratory abnormality

Renal failure, ARDS, hemorrhage from ovarian rupture, and thromboembolic

phenomenon are potential life threatening complication

hospitalization : frequent evaluate of vital signs, daily weight,abdominal circ.,fluid intake and output and serial Hct., electrolytes, renal and

liver function supportive treatment


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Risk factor ofovarian hyperstimulation syndrome

1.rapid rising of serum estradiol >2,500 pg/ml

2. large number of small and intermediate sized ovarianfollicles

fertility drugs use among nulliparous subfertility was associated

with increase incidence of borderline serous ovarian tumorbut

not with any invasive cancer

no evidence that fertility drug use increases overall breast

cancer risk


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Induction of ovulation with exogenous GnRH

GnRH therapy intravenous catheter for interval of 2-3 wk. orlonger

pulsatile fashion

low risk multiple pregnancy and ovarianhyperstimulation syndrome


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Pharmacology and physiology of exogenous GnRH treatment

GnRH is administer in continuous pulsatile fashion using

portable, programmable minipump

IV or subcutaneous

IV form dose , less cost, more physiologic andmore effective

rapid metabolized terminal half-life 10-40 minutes afterIV administration

IV form mimicpulsatile hypothalamic GnRH secretion


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Indication for exogenous GnRH treatment

anovulatory infertile women with hypogonadotropic

hypogonadism

other ovulatory disorder PCOS

hyperprolactinemia dopamine fail or can nottolerate


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Exogenous GnRH treatment regimens

most effective when administered intravenously in low doses

(2.5-5.0 microgram/pulse) at a constant interval (every 60-90min)

response higher dose 10-20microgram

dose Primary hypogonadotropic hypogonadism : low dose 2.5

microgram/pulse induce ovulation follicularphase LH concentration may remain lowerthan normal and

luteal phase progesterone concentration are often reducedhigher dose 5.0micrgram/pulse


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Exogenous GnRH treatment regimens cont.

Secondary idiopathic hypogonadotropic hypogonadism

sensitive GnRH therapy

GnRH dose PCOS pretreatment with long acting GnRH agonist (dailysubcutaneous administration) for 6-8 wks. Immediately before

starting pulsatile GnRH treatment


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ovulation support luteal phase

1.GnRH therapy can continue at the same or slower pulse

frequency every 120-240 min.

2.small dose of hCG : 2,000 IU every 3 days

3.exogenous progesterone


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Monitoring exogenous GnRH treatment

monitor superovulation time of ovulation


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Results of exogenous GnRH treatment

Ovulation rate 50-80%

Cycle fecundability 10-30%

Risk of multiple pregnancy in GnRH induced conception cycle is comparable to

that associated with clomiphene treatment (5-8%)

40-75% lower than that associated with exogenous gonadotropin therapy in

anovulatory women (15%)

incidence ofspontaneous miscarriage in exogenous GnRH induced conception

cycles is 30 %, miscarriage rate are lowest in hypogonadotropic hypogonadism

less than 20% and highest in PCOS >40%


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Induction of ovulation with dopamine agonists

Two most common bromocriptine and cabergoline

ergot alkaloid action mimic dopamine

Serum concentraton of bromocriptine peak 1-3 hr.

after an oral dose of bromocriptine and very little

remain in the circulation 14 hr. after administration

Cabergoline is a longer acting dopamine agonist with

high affinity for dopamine receptor, A single dose of

cabergoline effectively inhibit prolactin secretion 7

days or longer


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Mechanism of action of dopamine agonists

hyperprolactinemia hypothalamic-pituitary-ovarian

axis Dopamine agonist inhibitlactotrope prolactine secretion


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Indications for dopamine agonist treatment

drug of choice for hyperprolactinemic infertile women with

ovulation dysfunction who wish to conceive

galactorrhea normal serum prolactin level

>30% of PCOS can exhibit hyperprolactinemia dopamine agonist adjavant treatment exogenousgonadotropin treatment

pre-treatment dopamine agonist ovarianresponse exogenous gonadotropin


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Dopamine agonist treatment regimen

dose euprolactinemia

begins with dose of 1.25-2.5 mg, administered at bedtime to

more effectively suppress normal nocturnal increase in

prolactine secretion

low dose GI and cardiovascular side effectProlactin level decrease and stabilize shortly after treatment

begin : prolactin level 1 wk. aftertreatment

Cabergoline begins with dose 0.25 mg twice weekly, increase

gradually thereafter about every 4 wk. until the effective dose is

established


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Result of dopamine agonist treatment

normalizes and maintain normal prolactin level 60-85% of

hyperprolactinemic women

Cyclic menses are restored 70-90%, usually within 6 wk. after

treatment begin

Ovulatory cycle return 50-75% of treated women with or

without tumors

Breast secretion typically diminish 6 wk. and complete

cessation of galactorrhea generally takes about twice as long to

achive


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Side effects of dopamine agonist

2 Bromocriptine stimulate D1 and D2 receptor cabergoline highlyaffinity D2 receptormild adrenergic side effects; dizziness, nausea, vomiting, nasal stuffiness, and

orthostatic hypotension

1. low dose at start

2. taking medication with meal or snack

3. vaginal administration


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Risks of dopamine agonist treatment

No evidence that dopamine agonists pose any increase risk for

spontaneous miscarriage or birth defects


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induction ovulation

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