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Transcript of Delfi Lutan Induksi Ovulasi
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Induction ovulation with
gonadotrophins
Delfi Lutan
Department of Obstetrics & Gynecology
Medical School. University of SumateraUtara.
MEDAN, 15 September 2013
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Hypothalamic-Pituitary-Ovary Axis (HPO)
Hypothalamus
Pituitary Gland (Anterior)
LH FSH
Ovaries
GnRH
E2
P4
Androgens
Prolactin
F
ER
TILIT
Y
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WHO Classification of Anovulatory Patients
Serum gonadotrophins
and
serum E2 levels
FSH and LH
and
E2
FSH ~and
E2 ~
FSH and LHand
E2
WHO I WHO II WHO III
OI
IVF
OI
IVF
OI?
IVF?
egg donation
(~80%)(510%) (510%)
PCOS
Insler & Lunenfeld. New York: Churchill Livingston, 1972; WHO. Cambridge, Cambridge University
Press, 1993; ESHRE Capri Workshop. Hum Reprod 1996;11:1779807
E2, oestradiol; FSH, follicle-stimulating hormone; IVF, in v i t rofertilization; LH, luteinizing
hormone; OI, ovulation induction; PCOS, polycystic ovary syndrome
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Chronic Low Dose Protocol
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Merck Serono has led the development of
gonadotrophins for therapeutic use
Follicle-
stimulatinghormone
0
10
20
30
40
50
60
70
80
90
100
%
Pergonal
(menotrophins)
Metrodin
(urofollitrophin)
Metrodin HP
(highly purifiedurofollitrophin)
Gonal-F
(recombinanthFSH)
Luveris
(recombinanthLH)
Ovidrel
(recombinanthCG)
1960s Mid-1980s 1990s developments 2000
U-LH
Urinaryproteins
R-hLH
R-hCG
BIOLOGICALEXTRACTS
PURE MONO-
THERAPEUTICS
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Improved Ovarian Response
r-hFSH vs u-FSH in WHO Group II PatientsBalasch et al, 1998, J. Assisted Reprod. & Genetics
HP-FSH
20
15.8 1.8
17.2 2.81290 210
85.4 7.9
275 34
22.3 3.0
1.0 0.3
0.2 0.11.1 0.07
P Value
0.01
0.0030.003
0.05
0.009
0.002
NS
NSNS
Parameter
Cycles
FSH required
- Days of treatment
- Ampoules- IU
- Daily effective dose
Estradiol on hCG day (pg/ml)
Inhibin A on hCG day (pg/ml)
No of follicles on hCG day
11-13 mm
> 13-17 mm> 17 mm
rFSH
20
11.5 0.9
10.5 1.1787 90
73.9 6.1
473 82
48.2 7.0
0.8 0.2
0.4 0.31.2 0.1
%
-28%
-39%
N.S. = not s ign if icant
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Pregnancy Rates in IUI by
Different Treatment Methods(Buhler 2004 from 21 German Fertility Centres)
no stimulation
n=2150
Clomiphenen=5775
hMG
n=3298
FSH
n=18834
FSH+Antagonist
n=409
7,2 7,3
8,9
10,1
11,7
0
2
4
6
8
10
12
14
[%]
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What Dose of hCG Should be Used to Trigger
Final Follicular Maturation and Ovulation?
Typical criteria for hCG administration is when onefollicle >= 18mm no more than 3 in total >=16mm
(International rhCG OI study group Fertil Steril 2001)
Studies in WHO II patients used either 5 or 10000
IU u-hCG (Hedon et al 1998: Balasch et al 2000,2001: Hugues et al 2001)
With the availability of r-hCG it has beendemonstrated that 250 mcg r-hCG (Ovidrel) is aseffective as 5000 IU u-hCG with a lower incidence
of local adverse reactions
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Identities of contaminating molecules in
urine-derived human gonadotrophins
Transferrin1
Tumournecrosis factor-
binding protein1
Immunoglobulin derivatives1
Urokinase1
Epidermal growth factor1
Leukocyte elastase inhibitor
2
Protein C inhibitor2
Zinc-2-glycoprotein2
1. Giudice et al. Hum Reprod 1994;9:229122992. van de Weijer et al. Reprod Biomed Online 2003;7:547557
All are biologically
active proteins
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Induction of Ovulation in WHO Group II
Anovulatory Women Undergoing Follicular Stimulation with
Recombinant Human Follicle-stimulating Hormone: A Comparison of
Recombinant Human Chorionic Gonadotropin (rhCG) and Urinary hCGFert i l i ty and Steri l i ty Vol. 75, NO. 6, Jun e 2001
85 patients randomised received 250 mcg Ovidrel and 92receieved uhCG (5000 IU)
95% ovulated with Ovidrel
88% ovulated with uhCG Serum Progesterone levels luteal phase days 5-7 significantly
higher (P= 0.036) after Ovidrel administration
Clinical Pregnancy rate was 26%
Significantly higher incidence of local adverse reactions (P=0.039) including pain and inflammation with uhCG vs rhCG
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Is Luteal Phase Support Necessary in
Anovulatory Patients?
Routine luteal support is not normally applied in
OI cycles however some pateints who have a
history of a short luteal phase may benefit
from some form of support.
Low dose hCG is an effective form of luteal phase
support, but it has been associated with a higher
incidence of OHSS in FSH stimulated patients(Daya 2004)
Vaginal gel progesterone is easy for the patient to
self administer without above complications.
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Efficacy and Safety of Recombinant
Gonadotrophins
Summary
Urinary Gonadotrophins
No control on UrineDonors
Contain uncharacterizedhuman proteins
Poor batch-to-batchconsistency
Low specific activity
Recombinant FSH
Constant and fullycharacterised mammalian cell
Only contains human FSHprotein
Improved batch-to-batchconsistency
Increased specific activity
Increased purity Optimal approach for risk
reduction
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The Shape of Theraupeutics in Reproductive Health
Cetrotide
GnRH
Antagonist
Luveris
r-hLH
OvidrelR-hCG
Gonalf FbM
r-hFSH
Crinone
Vaginal
P4
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- 3 to 12 hours of the LH surge in dramatic change of
oocyte nucleus with breakdown of dictyatechromosomes and termination of the arrested meiotic
prophase
- The first meiotic division is completed with expulsion
from first polar body
- Preovulatory changes in the follicule include thinning
of its peripheral wall, increase of volume follicle and
finally follicle rupture
- Expulsion of the oocyte and cumulus through the
stigma of the follicle in known as ovulation
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Ovulation cont
This ovulation process occurs 10-12 hours after theLH peak, between 24-36 hours after the E2 peak.
LH surge is a more precise indicator to predictovulation.
LH surge occurs between 28 to 32 hours prior tofollicle rupture
Thirdly synthesis of prostaglandin have alson beeninplicated in ovulaton
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Ovulation cont 1
Followed endocrinological modification of follicular
cells the formation of corpus luteum
Follicle wall becomes convuluted
Granulosa cells enlarge
LH promotes luteinization from gralunosa whichresults in progesterone production
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Ovulation cont 2
The steroidogenic capacity of the corpus luteum
depend on the tonic LH levels
Progesterone production increases and reaches the
peak after 8 days of LH surge
Gonadotrophins levels decline rapidly to the basal
level as a result of negative feedback
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Ovulation cont 3
Oocytes were classified as
Preovulatory (fully mature)
Immature (viable eggs with the possiability ofmaturing)
Atretic (including oocyte with fracture of thezonal)
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Critical factors for high quality oocyte
production include
Patient age
Totat amount of gonadotrophins used
Time of hCG administration
Type of gonadotrophins used
Type of protocol used
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Various Ovarian Stimulation Regimes
Oral anti-estrogen medications
Gonadotropins
Gonadotrophin-releasing hormone (GnRH)
analogues (medical oophorectomy)
Pulsatile GnRH
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Are known by reproductive biologists since themiddle of 1920, in brief there are 3 gonadotrophins
The first is follicular stimulating hormone (FSH), to
stimulate follicular growth and ripening
The second is luteinizing Hormone (LH), with results
in follicle maturation leading to ovulation it also
regulates transformation of follicular remnants intofunctional corpora luteal
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Gonadotrophins cont 1
The third gonadotrophins is Human
Chorionic Gonadotrophin (hCG) and its
produced by trophoblastic cells; its
biological action similar to LH
Are glycoproteins with molecular weight
around 30,000 daltons.
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Gonadotrophins cont 2
Have been extracted from various sources
including human pituitary glands, pregnant
mare serum, urine of pregnant women, post-
mortem human hypophyses, human postmenopausal urine, from genetically
engineered hamster ovary cells
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1) those who do not ovulate regularly
and/or have failed to ovulate and/or
conceive with clomiphene
2) women who ovulate on their own but
may benefit from simultaneous ovulation of
multiple eggs and the accompanyingenhanced hormonal environment
Gonadotropins are used primarily in
two groups of women
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Gonadotrophin preparation available
Follicular Stimulating Hormone (FSH)
Human menopausal gonadotrophin (hMG)
Human Chorionic Gonadotrophin (hCG)
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Follicular Stimulating Hormone (FSH)
Urofollitrophin (pure FSH)
Recombinant human FSH
One ampoule consists of 75 iu or 150 iu
FSH (containing FSH, LH the ratio of
100:1)
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Human Menopausal Gonadotrophin
(hMG)
This is produced from post menopausal
urine.
Each ampoule contains 75 iu of LH and 75 iu
of FSH activity
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When ovulation is to be triggered
Administered, usually 24 to 48 hours after the
last dosage of hMG or FSH
The dose is either 5000 or 10,000 iu
The hCG has similar effects with LH but has
longer half life
Human Chorionic Gonadotrophin
(hCG)
R i G d t hi
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Regimes Gonadotrophins(Thomson and Hansen, 1970)
- Daily hMG is given overlapping with hCG for
the last 1 to 3 days, occasionally given
continously for 1 to 2 days after stopping
hMG
- Daily hMG followed by hCG from one to three
days, starting from 1 to 2 days after the last
hMG dose (not overlapping)
Regimes Gonadotrophins
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Regimes Gonadotrophins
(Thomson and Hansen, 1970)
- hMG on day 1,4, and 8 followed by hCG onday 11
- hMG with hCG administration at the end,either overlapping or not
- hMG alone
- hMG in a single large dose followed by hCGin day 11
- hMG combined with CC
Regimes gonadotrophins
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Regimes gonadotrophins(Jones et al, 1990)
Two ampoules of hMG were given beginning on day three of themenstrual cycle, and continued until a satisfactory response
Combo I, two ampoules of hMG were given beginning on day threeof the menstrual cycle, supplemented by two ampoules of FSH ondays three and four, until satisfactory response
Combo II, two ampoules of hMG were given beginning on daythree of the menstrual cycle, supplement by two ampoules of FSHon day three and four, with further supplementation FSH onsubsequent days, until a sastifactory response
4-4 FSH two ampoules of FSH were given beginning on day
three of the menstrual cycle, supplemented by two ampoules ofFSH on days three and four, until a sastifactory response wasobtained
Two ampoules of FSH were given beginning on day three of themenstrual cycle, supplemented by other FSH beginning on day
three, until a satisfactory response.
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Regimes gonadotrophins(Serono, adopted from drug information)
Alternate day therapy. Treatment with hMG on threeanternate days followed by hCG on day 8 of thecycle
Daily therapy, hMG given daily with treatment for 7days, followed by hCG 24 to 48 hours after the lastdose of hMG
Treatment with pure FSH. Is given 8 to 10 days, alsothrough combination of FSH and hMG can be given.Once adequate E2 concentration is reached, hCGcan be administration
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Regimes gonadotrophins(Lutan D, 1993)
Combination of CC+hMG, 50-100 mg cc and 1 ampoule hMGdaily from day 2 until hCG (5000 IU) administration
Combination of CC+FSH, 50-100 mg cc and 75 IU (1 ampoule)FSH daily from day 2 until hCG (5000 IU) adminstered
Human menopausal gonadotrophin (hMG) alone, 225 IU FSH and225 IU LH (3 ampoules) daily from day 2 until hCG (5000 IU)adminstration
Pure follicular stimulating hormone (FSH), 225 IU (3 ampoulesFSH) daily from day 2 until hCG (5000 IU) administered
Combination of FSH + hMG, 2:1, 2 ampoules of FSH and 1ampoules of hMG were administered daily from day 2 of thecycle for 5 days, thereafter only hMG was given and the dosedepended on the response of the patients until hCG (5000 IU)administration
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Regimes gonadotrophins(Jamaan T and Anwar NC,2006)
Clomifen citrate and hMG sekuensial
Flare protocol and FSH/hMG
Fixed dose regiment FSH/hMG
Protocol antagonist and FSH
R i d t hi
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Regimes gonadotrophins(Speroff L and Fritz MA, 2005 )
Step-up Regimen, begin low daily dose (75 IU). After4 to 7 days of stimulation the dose ofgonadotrophins may be maintained or increaed.When the mean diameter of the lead follicle reaches15-18 mm, hCG is adminstered to trigger ovumrelease
Step-down regimen, treatment begins with a higherdose (150-225 IU daily)
Sequential treatment with clomiphene andgonadotrophins, 50-100 mg daily cc, followed bylow-dose FSH or hMG (75 IU daily)
Adjuvant treatment with GnRH
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Gonadotrophin-releasing hormone (GnRH)
analogues with gonadotrophins
The potent GnRH analogues are able to reduce thelevels of endogenous gonadotrophis, to suppressthe positive LH feedback mechanism and increasethe number of follicles (medical oophorectomy)
Administered in three protocols, the long, the shortand the ultrashot
Another respectively termed as the flare-down, theflare-up and the ultra-shot
Gonadotrophins, with hMG.
M i i d hi
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Monitoring gonadotrophin
therapy/prediction of ovulation
Serum oestradiol levels
Luteinizing hormone (LH) surge
Ultrasonography Basal body temperature
Cervical mucus
Mittelschmerz
Vaginal squamous epithelium
Human Chorionic Gonadotrophin (hCG)
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Human Chorionic Gonadotrophin (hCG)
adminstration
Objectives of hCG administration are to initiate final
oocyte maturation and normal corpus luteumformation
Disadvantages encountered involve the maturity of thefollicles when the hCG is given and the time of interval
between the injection and ovulation
These two factors are closely related. Follicular growthis usually monitored by daily serum or urinaryoestradiol and ultrasonography
The time interval between the injection hCG andovulation, 32-42 hours after injection
Doses hCG, for initiating ovulation was 5000 IU.
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Luteal Phase Support
First regime progesterone 25 mg im, wasgiven daily from the 5th day (day 0 being theday of preovulatory) to the 16th. Blood testB-hCG was done on the 14th and 16th day
The other luteal support regime was hCG1000IU on days 4,7,10 and 13 afterpreovulatory. Blood test was done on the16th and 18th day
C li ti f d t hi
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Complication of gonadotrophin
therapy
Multiple pregnancy abortion, neonatal deathsand congenital abnormalities
The hyperstimulation syndrome, mildhyperstimulation is a common finding andhas no clinical significance
Hyperstimulation may be catagories intomild, moderate and severy
Grades of hyperstimulation
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Grades of hyperstimulation(Rabau et al, 1967)
A. Mild, 1.urinary oestrogen above 150 ug and
urinary pregnandiol above 10 mg, but no palpablecyst or enlargement of ovaries. 2. Enlargement ofovaries with or without palpable cyst formation
B. Moderate, 3. enlargement of ovaries or cyst,
distention of abdomen, nausea. 4. Enlargement ofovaries of cyst, distention of abdomen, nausea,vomiting and/or diarrhea
C. Severe, 5. Enlargement of ovarian or cysts,include distention of abdomen, nausea, vomitingand/or diarrhoea, plus fluid in abdomen and/orpleura. 6. Same as group 5 plus change in bloodvolume, viscosity and coagulation time.
Grades of hyperstimulation
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Grades of hyperstimulation(NG, at al, 1991 based on WHO, 1973)
Mild, oestradiol (E2) of at least 1500 pg/ml, and
ultrasonic evicence of at least 10 follicles and no lutealphase complications
Moderate, with luteal problems of enlarged, painful
ovaries, high oestradiol of at least 3000 pg/ml, ascitesof less than 1.5 liters, and without grossly distendedabdomen
Severe, with grossly distended abdomen due toexcess ascites and possible hydrothorax. May beassociated with fluid-shift problems resulting inhaemoconcentration, hyper-coagulopathy andelectrolyte changes. Requires hospitalisation and may
require paracentesis
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