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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%3Dth7/27/2019 Induction Ovulation
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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%3Dth7/27/2019 Induction Ovulation
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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%3Dth7/27/2019 Induction Ovulation
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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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