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Definitions

• 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
• 90 of couples should conceive after 12 mo. Of
  unprotected intercourse

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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

• 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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Ovulation Hormonal control
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Ovulation dysfunction
Ovarian Central
Hypogonadotrophic Hypogonadism Group I
Anovulation PCOD Group II
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Induction of Ovulation

• Use of medications to induce the
• development of ovarian follicles
• as needed for
• - Controlled Ovarian Hypestimulation
  (COH)
• Group I and Group II
• Unexplained
  infertility
• Age related
  infertility
• - In Vitro Fertilization

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Induction of ovulation

• Clomiphene citrate
• Exogenous gonadotropins
• Exogenous GnRH

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Induction of ovulation with Clomiphene Citrate
Drug of choice for chronic anovulation group II

• Clomiphene citrate first synthesized in 1956
• Approved for clinical use on 1967
• Anovulatory women who use Clomiphene Citrate
  
• - 80 ovulation
• - 70 of ovulated conceive

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Pharmacology of Clomiphene

• Nonsteroidal triphenylethylene affinity to E
  receptor
• (estrogen agonist and antagonist properties)
• Main action is as an anti-estrogen
  (Hypothalamus, Endometrium, Cervical mucous)
• Estrogenig affect Hypophysis (Facilitate FSH
  secretion)

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CC at the Hypothalamus

• Competitive inhibitor of E2
• Blocks E receptor in hypothalamus.
• Interfere with receptor recycling
• GnRH FSH LH
  Folliculogenesis

Endometrium Can be thinner Cervical mucous -
dysmucorrhea
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Clomiphene treatment regimen

• Administer orally (day 5-9) 50 mg tablets
• To start - Progestin induced menses
• Ovulation takes place day 14-16
• Startig dose 50 mg tablet daily
• Spontaneous or induce ovulation by hCG
• Follow-up by US Estradiol level

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Clomiphene treatment regimen
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Results of Clomiphene treatment

• Successfully induce ovulation in approximately
  80
• Overall cycle fecundity is 15
• Cumulative pregnancy rates of 70-75 can be
  expected over 6-9 cycles of treatment

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Side Effects of Clomiphene

• Minor side effects are common
• transient hot flushes 10, vasomotor symptoms,
  and mood swing
• 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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Risks of clomiphene treatment

• Multiple pregnancy risk increased to 5-8
• Congenital anomalies no substantial evidence to
  be increased
• Miscarriage no difference
• Ovarian hyperstimulation syndrome
• Incidence of borderline serous ovarian tumors
  but not with any invasive cancers

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Gonadotropins

• Unlike CC Gn acts directly on the ovaries.

Indications Failed CC Hypo
Hypo Unexplaine infertility
Assisted Reproductive Technology (ART)
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Exogenous Gonadotropins

• HMG (Menogon, Menopur)
• Highly purified uFSH
• Rec. FSH (Gonal-F, Puregon, Elonva)
• Rec. LH (Luveris)

FSH acts directly on the ovary to induce
folliculogenesis LH can be added when needed
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Advantages of Recombinant Human Gonadotropins

• Better batch-to-batch consistency
• Steady supply.
• A purified compound
• Well tolerated (S.C)
• No antibodies formation

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Mode of treatment
1 2 3 4 5 6 7 8
9 10 11 12 13 14 15 16 17
18 19 20 21 22 23 24 25 26
27 28 29 30
GN
GN
Insemination Intercourse
COH 2-3 follicles
hCG
Adjusted dose
Monofollicular Mild stimulation
OHSS
Endometrium
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Hypogonadotropic Hypogonadism
Drug of choice is menotropins contain
both FSH and LH
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Failed CC - PCOD

• Susceptible to OHSS
• Chronic low dose of GN
• Monofollicular ovulation

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Result of exogenous gonadotropin treatment

• Successfully induce ovulation in almost 100
• Hypogonadotropic hypogonadism
• Cycle fecundity rate 25, equal or greater than
  normal fertile women
• Cumulative pregnancy rate after 6 mo - 90
• Clomiphene resistant anovulation and
• Unexplained infertility
• Cycle fecundity rate 5-15
• Cumulative pregnancy rate after 6 months - 30-60

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Risks of gonadotropin treatment

• Multiple pregnancy
• Ovarian Hyperstimulation Syndrome
• (OHSS)

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Complications of gonadotropin treatment
Multiple pregnancy Spontaneous 1
(Twins) Clomiphene induce 5-8 Gonadotropin
15-30 Normal frequency of monozygotic twin
0.3-0.4, increase 3 fold with exogenous
gonadotropin Spontaneous miscarriage - 20-25,
moderately higher than general rate of
15 Clomiphene and gonadotropin no congenital
anomalies
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Summary

• Familiar with strong tool to induce ovulation
• Should be used adequately with proper
  indications
• The art of treatment to prevent complications
• Use the roper combination to reach your goal
• (CC for group II, Urinary Gn, recombinant,
  rLH)
• Use in combination with GnRH analogues
• (agonists and antagonist) for IVF

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GnRH
Natural

• -Is a deca peptide ( ten AA ).
• -Half life time is 8 min (10 min bursts
  every 60 min)
• By selective A.A or ethylamide substitutions at 6
  and/or 10 (Gly) postions.
• - ? affinity for GnRH receptors (100-200
  times).
• - ?1/2 life to 5 hours.

Synthetic
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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

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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 and more effective
• rapid metabolized ????? terminal half-life 10-40
  minutes after IV administration
• IV form mimic pulsatile 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 not tolerate

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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 60-90 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

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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 (daily subcutaneous 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 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

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GnRHa

• Advantages
• Prevent the possibility of premature LH surges
  (as a result of ? E in response to Gn)??cancealed
  cycles.
• Suppression of endogenous basal LH levels
  ?recruitment of a larger cohort of follicles.
• Decrease LH stimulation of ovarian androgen
  production (may interfere with follicular
  development)
• Allow better timing of oocyte retrival
  synchronise follicular growth.

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GnRHa

• Routes
• - Intranasal.
• - S.C.
• - Depot (Longer period need higher doses Gn
  need more luteal support) (Devreken et al ,1996).
• Effect
• - Agonistic (flare up) phase ??LH FSH .
• - Down regulation (on continuous administration)
  Within two weeks).

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GnRH Antagonist

• Chemically it is also a decapeptide with changing
  the aminoacid sequense at positions 1,2,3,6 and
  10.
• When GnRH antagonist is applied for short period
  it leads to abortion of LH peak, diminished E2
  production and impairment of follicular growth.

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