Seminar

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Seminar Induction of ovulation

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• Infertility 1 year of unprotected intercourse
  without pregnancy
• Primary infertility no previous pregnancy has
  occurred
• Secondary infertility infertility prior
  pregnancy, although not necessary a live birth
• Fecundability is the probability of achieving
  pregnancy within a single menstrual cycle
• Fecundity is the probability of achieving 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 of infertility

• 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) and fall again to
  baseline just before or onset of mense
• Call Biphasic pattern ovulation
• Thermogenic shift when progesterone gt 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 phase
• Rise slightly on the day of LH surge 1-2 ng/ml
• Peak 7-8 day after ovulation then decline before
  mense
• Level gt 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 one
  best day for times intercourse and artificial
  insemination

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Evaluation before induction of ovulation

• ???????????????????????????? anovulation
  ??????????????????? ???????????????? thyroid
  disease, hyperprolactinemia, adrenal disease,
  pituitary or ovarian tumors, extremes of weight
  loss or exercise, polycystic ovary syndrome and
  obesity
• chronic anovulation ????? risk ??????????
  endometrial hyperplasia and neoplasm ????????????
  endometrial sampling ????????? irregular mense

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Classification of ovulation disorders

• Group 1hypothalamic-pituitary failure
  hypothalamic amenorrhea ?????????????? stress,
  weight loss, exercise, anorexia nervosa and its
  variants, Kallmann syndrome and isolated
  gonadotropin deficiency ??????????? hypothalamic
  or pituitary mass lesion
• Labs low FSH and estrogen level ??? normal
  prolactin concentration

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• Group 2hypothalamic pituitary dysfunction
  
• amenorrhea or oligomenorrhea with or without
  associated hyperandrogenism PCOS with
  anovulation
• Labsnormal FSH, estrogen and prolactin
  concentration
• Group 3ovarian failure
  
  
• amenorrhea
  
  
• elevated serum FSH

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Evaluation of other infertility factors

• Before ovulation induction should screening semen
  analysis because infertility ??? male factor
  ???????? 20-40 ???????????? coexist ??????????
• preliminary evaluation with HSG or transvaginal
  ultrasonography when
• -history of previous pelvic infection or
  surgery, ectopic pregnancy, inflammatory bowel
  disease, pelvic pain or other symptom of
  endometriosis or an 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
  should preliminary evaluation
• recommended preliminary HSG and transvaginal
  ultrasonography when medical history or physical
  examination suspected coexisting uterine or tubal
  infertility factors, age over 35, 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 gonadotropins
• Exogenous 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
  1967
• anovulatory women who recieve clomiphene citrate
  
• -80 ovulation
• -50 of ovulated conceived

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Pharmacology of Clomiphene

• nonsteroidal triphenylethylene derivertive
  ????????? estrogen agonist and antagonist
  properties
• Main act purely as an antagonist or anti-estrogen
  ???? weak estrogenic action
• metabolism ?????? ??????????????????? 85
  ???????????????? 1 ???????
• 2 different stereoisomers
• 1.enclomiphene 2.zuclomiphene

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Mechanism of action

• compete ??? estrogen ??????????????? nuclear
  estrogen receptor
• ?????? receptor ??????? ????????????? receptor
  ????? interfere receptor recycling
• hypothalamus???????? depletion ??? estrogen
  receptor ???????? interpretation of estrogen
  level ????????? ???????????????? ??????? estrogen
  negative feedback ???????????????? GnRH secretion
  ? 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 mucus
• 2.serum estradiol determination (gt40pg/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 infertility???????????????????????????
  ?????? infertility ???? ?????????? aggressive
  treatment
• Empiric clomiphene treatment ?????????????????????
  ???????????????? intrauterine insemination

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Clomiphene treatment regimen

• Administer orally ?????????????? 3-5
  ????????????????????????? ???? progestin induced
  menses
• amenorrheic 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 women LH 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 mature preovulatory follicles

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Results of Clomiphene treatment

• successfully induce ovulation in approximately
  80 of properly selected women
• overall cycle fecundability is 15 ??anovulation
  ??? ovulate ??????????? clomiphene treatment
• Cumulative pregnancy rates of 70-75 can be
  expected over 6-9 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 cycle fecundability
• 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 every 15-20
  treatment cycles

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Side Effects of Clomiphene

• Minor side effects are common
• transient hot flushes ???? 10,vasomotor
  symptoms, mood swing 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 lt2
  but reversible

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Peripheral Antiestrogenic effects of Clomiphene

• ??????? peripheral sites in reproductive system
  ???? endocervix, endometrium, ovary, ovum and
  embryo
• Cervical mucus cervical mucus production ????
• Endometrial growth and development ???????
  estrogen mediated endometrial growth ????????????
  minor effect or ?????????
• peak preovulatory endometrial thickness lt 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
  ?? nulliparous subfertile women ??????? incidence
  of borderline serous ovarian tumors but not with
  any invasive cancers

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Treatment options after clomiphene failure

• Clomiphene failure ??? failure to ovulate in
  response to clomiphene treatment
• Many 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 5 days treatment regimen)
• 2.adjuvant treatment with glucocorticoids or
  exogenous human chorionic gonadotropin
• 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

• gt50 ??????????? response ??? standard 5 day
  treatment regimen(150 mg daily) ?? ovulate after
  longer duration of clomiphene treatment (7-10
  days)

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Clomiphene and glucocorticoids

• ???????????????????? ?????? induce ovulation
  ??????????? fail to response to clomiphene alone
• most efficacious in women having elevated serum
  dehydroepiandrosterone sulfate (DHAS)
  concentration and also effective in those with
  normal DHAS and unselected populations of
  clomiphene resistant women
• Mechanism of glucocorticoid action remain unclear
  
• combined treatment 3-6 cycles ???????????????
  ?????????????????????????

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Clomiphene and hCG

• Exogenous hCG ???????????? LH surge
• ????????????????? IUI ????????????????
  unexplained infertility and with coexisting male
  factor
• ??? transvaginal ultrasound ??????????????
  follicles ??? mature for ovulation ???????
  ??????????? hCG ???????? follicles ?????? mature
  follicles ????? induce atresia ??????? ovulation
• peak preovulatory follicular diameter in
  successful clomiphene induced ovulatory cycles
  ranges between 18-30 mm(mean 25 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 urinary LH surge detection
• Exogenous hCG can be useful fail to detect the LH
  surge
• Ovulation occurs 34-46 hrs after hCG injection
  ??????? IUI usually 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 resistant anovulatory
  women
• ???????????????? ovulation rate excess 70 and
  cumulative pregnancy rate over 50

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Insulin sensitizing agents

• Anovulation infertile women with PCOS and
  hyperinsulinemia ????????????????????????
  clomiphene
• ????????????????????????????? 5 ???????
  ovulatory cycle ??????????????
• ???????? screening for impaired glucose tolerance
  and diabetes
• PCOS ???? insulin resistance ?????????????
  insulin sensitizing agent ????????????????????
• 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
  anovulation
• Metformin 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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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 function
• 40-90 of women have ovulated after laparoscopic
  ovarian drilling and at least half of those have
  conceived

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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 gonadotropin have been used for more
  than 40 years to 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
  premenstrual spotting, grossly short luteal
  phase, and endogenous LH less than 3 IU/L
• ??????????? luteal support supplemental
  hCG(2,000-2,500 IU 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 hypogonadism ???
  clomiphene 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
• ??????????????? superovulation
• ??? dose ????????????????
• 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 ?????
  serum estradiol level with or without
  transvaginal sonography
• ??????????? PCOS ???????????? exogenous
  gonadotropin ???????? ??????????????????????
  ?????????????? mornitor ????????

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1.Step-up regimen cont.

• Ovarian hyperstimulation ?????????????????
  ?????????????????????? low slow treatment regimen
  
• ???? gonadotropin stimulating span 7-12 ???
• PCOS ????? low dose ??? longer duration ?????????
  metformin ????????????????? gonadotropin??????
  improve response

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2.Step-down regimen

• ??????????? high dose (150-225 IU daily) and
  decrease gradually
• ?????? regimen ??????????????? response threshold
  ?????????????????? one or more previous
  stimulating cycles

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3.Sequential treatment with clomiphene and
gonadotropins

• clomiphene resistant anovulation ???????
  unexplained infertility ???? benefit
• Typical 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 gonadotropin stimulation ?higher
  incidence of spontaneous miscarriage
• preliminary treatment with long acting GnRH
  agonist before exogenous gonadotropin stimulation
  prevent premature luteinization
• risk ????????? poor luteal function ?????????????
  residual GnRH 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 decline
• dominant 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 limited
• hypogonadotropic hypogonadism or PCOS
  recombinant LH treatment (225-450 IU daily)
  during latter stages of follicular development
  can decrease the number of developing follicles
• little effect on circulating progesterone and
  testosterone concentration and risk of causing
  premature luteinization or other adverse effect
  is low

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Monitoring gonadotopin therapy

• To achieve ovulation but also avoid ovarian
  hyperstimulation and minimize the risk for
  multiple pregnancy
• serial serum estradiol measurements and ovarian
  ultrasonography

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Serum estradiol level

• ????????? follicles ????????????????? 10 mm
  ????????????? estrogen ???????????
• estradiol ???????????????? exponential
  ??????????? 2 ???? ?????? 2-3 ?????????? follicle
  ?? mature
• natural ovulatory cycle, estradiol peak 200-400
  pg/ml just before LH surge
• existing gonadotropin stimulation regimen, best
  results when estradiol concentration peak
  500-1,500 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
  5-7
• dominant 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
  diameter
• Follicle lt14 mm rarely ovulate
• 15-16 mm ovulate 40
• 17-18 mm ovulate 70
• 19-20 mm ovulate 80
• all larger follicle will ovulate

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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 gt90 either
  hypogonadotropic hypogonadism or clomiphene
  resistant anovulation
• Hypogonadotropic hypogonadism
• Cycle 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
• spontaneous 1.25
• clomiphene induce 5-8
• gonadotropin 15-30
• Normal frequency of monozygotic twin 0.3-0.4,
  increase 3 fold with exogenous gonadotropin
• Incidence of spontaneous 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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Multiple pregnancy

• risk ?????????? twin 1.older aged 2.use of
  exogenous gonadotropin for ovulation induction
  3.superovulation 4.ARTs
• ???????????? 1.preterm delivery 2.low birth
  weight 3.gestational diabetes 4.preeclampsia
  5.associated with high infant morbidity and
  mortality
• ??????? ovarian stimulation ?????????
  ??????????????
• 1.cycle cancellation
• 2.conversion to IVF and transvaginal aspiration
  of excess follicles

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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 pregnancy
  ????????????????? 3 ???
• 1.termination of entire pregnancy
  ???????????????????
• 2.continuing pregnancy ?????????????
  risk????????? preterm birth, increase neonatal
  morbidity and mortality and long term disability
• 3.multifetal pregnancy reduction

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Ovarian hyperstimulation syndrome

• ?????????????
• 1.ovulation induction with exogenous
  gonadotropin
• 2.clomiphene induced cycle
• 3.spontaneous pregnancy associated with
  condition characterized by supraphysiologic
  concentration of hCG (multiple gestation or molar
  pregnancy)

68
Pathophysiology of Ovarian hyperstimulation
syndrome

• ovary ??????????????? vasoactive substance ????
  vascular endothelial growth factor, element of
  renin-angiotensin system and other cytokine
  ?????????? capillary permeability ???? fluid
  shift 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
  affected women to sign and symptoms of
  progressive illness

72
Modarate symptom

• persistent and worsening symptom or ascites
  ?????????? progression of illness
• ???????? antiemetics and potent oral analgesics
• ???????????????????? OPD ??????? careful
  monitoring of daily 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

74
Risk factor of ovarian hyperstimulation syndrome

• 1.rapid rising of serum estradiol gt2,500 pg/ml
• 2.??????? large number of small and intermediate
  sized ovarian follicles
• fertility drugs use among nulliparous
  subfertility was associated with increase
  incidence of borderline serous ovarian tumor but
  not with any invasive cancer
• no evidence that fertility drug use increases
  overall breast cancer risk

75
Induction of ovulation with exogenous GnRH

• GnRH therapy ??????? intravenous catheter for
  interval of 2-3 wk. or longer
• pulsatile fashion
• low risk ?????????? multiple pregnancy and
  ovarian hyperstimulation syndrome

76
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 and more effective
• rapid metabolized ????? terminal half-life 10-40
  minutes after IV administration
• IV form mimic pulsatile hypothalamic GnRH
  secretion

77
Indication for exogenous GnRH treatment

• anovulatory infertile women with hypogonadotropic
  hypogonadism
• other ovulatory disorder ???????????????????????
• PCOS
• hyperprolactinemia ?????????? dopamine ???? fail
  or can not tolerate

78
Exogenous GnRH treatment regimens

• most effective when administered intravenously in
  low doses (2.5-5.0 microgram/pulse) at a constant
  interval (every 60-90 min)
• ?????????????????????? response ??? higher dose
  10-20 microgram
• ??????????? dose ???? ????????????????????????
• Primary hypogonadotropic hypogonadism low dose
  2.5 microgram/pulse ???????? induce ovulation
  ?????? follicular phase LH concentration may
  remain lower than normal and luteal phase
  progesterone concentration are often reduced
  ????????????????????????????????? higher dose 5.0
  micrgram/pulse

79
Exogenous GnRH treatment regimens cont.

• Secondary idiopathic hypogonadotropic
  hypogonadism ?????????????????????????? sensitive
  ??? GnRH therapy ??????????????? GnRH ???? dose
  ???????
• PCOS ??? pretreatment with long acting GnRH
  agonist (daily subcutaneous administration) for
  6-8 wks. Immediately before starting pulsatile
  GnRH treatment

80

• ??????????????? 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

81
Monitoring exogenous GnRH treatment

• ??????? monitor ?????????????????? superovulation
  ????
• ???????????? time of ovulation

82
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 of spontaneous miscarriage in exogenous
  GnRH induced conception cycles is 30 ,
  miscarriage rate are lowest in hypogonadotropic
  hypogonadism less than 20 and highest in PCOS
  gt40

83
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

84
Mechanism of action of dopamine agonists

• hyperprolactinemia ??????? hypothalamic-pituitary-
  ovarian axis ?????
• Dopamine agonist ?? inhibit lactotrope prolactine
  secretion

85
Indications for dopamine agonist treatment

• drug of choice for hyperprolactinemic infertile
  women with ovulation dysfunction who wish to
  conceive
• ???? galactorrhea ????? normal serum prolactin
  level
• gt30 of PCOS can exhibit hyperprolactinemia
  ?????? dopamine agonist ???? adjavant treatment
  ??????? exogenous gonadotropin treatment
• pre-treatment ???? dopamine agonist
  ??????????????? ovarian response ??? exogenous
  gonadotropin

86
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
  effect
• Prolactin level decrease and stabilize shortly
  after treatment begin ??????????? prolactin
  level ??????? 1 wk. after treatment
• Cabergoline begins with dose 0.25 mg twice
  weekly, increase gradually thereafter about every
  4 wk. until the effective dose is established

87
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

88
Side effects of dopamine agonist

• ???????????? 2 ??????????
• Bromocriptine ?? stimulate D1 and D2 receptor
  ???? cabergoline ?? highly affinity ??? D2
  receptor
• mild 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

89
Risks of dopamine agonist treatment

• No evidence that dopamine agonists pose any
  increase risk for spontaneous miscarriage or
  birth defects

90
The end