LH Surge

Report
PROF.DR.MEHMET ÇOLAKOĞLU
SELCUK ÜN.MERAM TIP FAK.
KADIN HAST VE DOĞUM ABD
IUI-Tarihçe
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İlk yayın 1790 John Hunter
İlk gebelik 1838 Girault F.
Donör inseminasyon 1884 Pancost W
Yıkanmış sperm 1950 Hanson FM, Rock J
Dondurulumuş sperm 1953 Bunge ve
Sherman
Split ejekulat 1960 Farris E
İlk randomize kontrollü çalışma 1984
Kerin JFP
IUI-Endikasyonlar
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Hipospadias
Vaginismus
Retrograd ejekulasyon
İmpotans
Servikal faktör
Subfertil erkek
Açıklanamayan infertilite
Endometriozis
Endikasyonlar
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Penis ve vajinanın anatomik ve
fonksiyonel bozuklukları
Servikal faktör
Erkek infertiltesi
İmmunolojik infertilite
İzah edilemeyen infertilite
Husband is away from wife for long time
(work abroad)
HIV negative women with processed semen
of HIV +ve husband.
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Kadın yaşı
İnfertilite süresi
İnfertilite tipi
Sperm kalitesi
Kateter tipi ve spermlerin transfer zorluğu
Matür folikül sayısı
Prematur LH önlenmesi
HCG gününde E2 konsantrasyonu
12,00
11,80
10,00
9
8,00
6,00
4,00
IUI başarısı (%)
2,00
0,00
Siklus
başına
gebelik
oranı
Siklus
başına
canlı
doğum
oranı
Annual report of the French Biomedicine
Agency 2005. www.agence-biomedecine.
IUI ve/veya KOH
• Doğal siklus
+
Koitus
• Doğal siklus
+
IUI
• Kontrollu ovaryen
stimulasyon
+
Koitus
• Kontrollu ovaryen
stimulasyon
+
IUI
KOH + IUI Kadının Yaşı Etkili mi?
Retrospektif analiz
168 olgu, 469 siklus, CC+hMG, hMG, FSH)
Yaş
<40
40
41
42
43
44
45
Siklus Sayısı
210
135
114
84
56
45
18
Gebelik (%)
18
13,3
7,9
4,8
1,8
0
0
40-42 yaşında klinik gebelik maliyeti KOH+IUI 30,000$
IVF-ET 77,000$
Corsan G, 1996
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AVANTAJLAR
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DEZAVANTAJLAR
› Ucuz
› Kısa sürede
› Gebelik oranı düşük
› OHSS
uygulama
› IVF-ET’ye bağlı
risklerden kaçınma
› Çoğul gebelik
› Enfeksiyon
› Premature LH riski
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Involves a poorly-understood neuroendocrine
phenomenon in which there is a switch from
negative feedback control of LH secretion by
estradiol and progesterone to positive feedback
Rising estradiol levels at the end of the
follicular phase result in a 10-fold increase in
serum LH concentration
Pulsatile activity of GnRH
neurones
“GnRH pulse
Hypothalamus
generator”
GnRH
Pulses of GnRH
Pituitary
Ovaries
+
LH
FSH
Pulses of LH
24 hours
Plasma LH
Ehrmann
NEJM
2005
Ovulation
trigger = LH surge
occurs ~12 hr prior to ovulation
Specific actions of LH:
(i) Stimulates completion of first meiotic division – can
be seen by ??
(ii) Stimulates progesterone production by granulosa
cells –
(iii) Stimulates increase in antral fluid volume
(iv) Stimulates release of hydrolytic enzymes (stigma)
(v) Stimulates follicular production of prostaglandins
What is this?
Trigger #1: LH Surge
Fig. 28-17 T&G
starting point = oogonium; during
embryonic development, oogonia
multiply to make many 10 oocytes
10
oocytes arrested at diplotene stage
of meiotic prophase  DNA
replicated and homologous pairs
aligned
each oocyte will stay at this stage
(or degenerate) until resumption of
meiosis is triggered by the
preovulatory LH surge
Trigger #2: Fertilization
Minor FSH Surge at Ovulation
(i)
Ensures sufficient LH receptors for luteal phase
(ii) Stimulates synthesis of hyaluronic acid  cumulus expansion
RESULT: oocyte + cumulus cells released into peritoneal cavity;
guided into oviduct by oviductal fimbriae
25
Evidence based recommendations for
practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004
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Where intra-uterine insemination is used to manage
unexplained fertility problems, both stimulated and
unstimulated intra-uterine insemination are more
effective than no treatment. However, ovarian
stimulation should not be offered, even though it is
associated with higher pregnancy rates than
unstimulated intra-uterine insemination, because it
carries a risk of multiple pregnancy.
Controlled ovarian hyperstimulation
before IUI
The rationale
•  Number of oocytes available
(  chance of fertilization )
•  Steroid production
(  chance of implantation )
• It may correct subtle ovulatory disorders, such as
luteinized unruptured follicle syndrome, not detected
with routine diagnostic studies
• More exact time to ovulation and insemination can be
determined
In possibly 5-20% (1 in 20 to 1 in 5) of women
undergoing menotropin therapy there may be a
premature LH surge. If this occurs, the use of a
GnRH agonist such as Lupron or Synarel
should prevent a spontaneous LH surge
(ovulation) in future cycles. These medications
(GnRH agonists) suppress the ovaries so that
higher dosages of menotropins are usually
required to accomplish multiple follicular
development.
There is apparently a natural substance (not yet
identified) that inhibits ovulation during the
maturation of eggs. In a natural cycle, the signal
from the brain to the ovary to trigger ovulation (the
LH surge) appears to occur once the serum estradiol
level reaches a certain concentration (about 250
pg/mL) for a certain length of time (about 2 days). In
a cycle of controlled ovarian hyperstimulation using
menotropins, the serum estradiol level may be
greater than 250 pg/mL for much longer than a week
without triggering ovulation. Therefore, the
existence of a natural “ovulation inhibitor” has been
postulated.
Ovarian gonadotrophin surge-attenuating
factor (GnSAF): where are we after 20
years of research?
Fowler PA, Sorsa-Leslie T, Harris W, Mason HD.
Source
Department of Obstetrics and Gynaecology, University of Aberdeen,
Aberdeen AB25 2ZD, UK. [email protected]
FSH was found to stimulate the ovarian production of an uncharacterized hormone
known by its specific effect of reducing pituitary responsiveness to GnRH. This
hormone has been called gonadotrophin surge-attenuating factor (GnSAF),
gonadotropin surge-inhibiting factor (GnSIF), various abbreviations (GnSAF/IF,
GnSIF/AF) and also attenuin. Although first described in the 1980s, GnSAF has still
not been convincingly characterized and no published candidate amino acid
sequences conclusively relate to GnSAF bioactivity. On the basis of
superovulation studies and in vitro experimentation into the roles of
steroids in regulating LH, GnRH and GnRH self-priming, the concept that
GnSAF has a role in the regulation of LH secretion, the timing of the LH
surge and the prevention of premature luteinization developed. For at
least a decade, understanding of the specific GnSAF effects of reducing
pituitary sensitivity to GnRH, especially GnRH self-priming and
antagonizing the stimulatory effects of oestradiol on GnRH-induced LH
secretion, supported this concept. However, improved knowledge of the changes
in GnSAF bioactivity in follicular fluid and serum in women requires revision of this
concept. The present authors propose that the main role of GnSAF is probably the
negative regulation of pulsatile LH secretion, mainly during the first half of the
follicular phase, indicating a critical role in the regulation of folliculogenesis and
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PREVENTION OF PREMATURE LH SURGE
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Despite the theoretical advantages of GnRH antagonists, their
use was hampered due to the results obtained in a Cochrane
review of the initial five randomizedstudies, which indicated
a trend towards slightly lower implantation and pregnancy
rates forthe GnRH antagonist treatment group compared to
those in the GnRH agonist group (Al-Inany and Aboulghar,
2002). The most recent Cochrane review (Al-Inany et al.,
2006), has included 27 randomized controlled trials (RCT),
and still shows similar results: clinical pregnancy rate was
significantly lower in the antagonist group and the ongoing
pregnancy/live-birth rate showed the same significantly
lower pregnancy in the antagonist group.
However, another recently published meta-analysis
(Kolibianakis et al., 2006) based on the analysis of 22
published RCTs, compared the effectiveness of GnRH agonist
and GnRH antagonists in IVF with respect to the probability
of live birth per patient randomized, and concluded that the
probability of live birth between agonists and antagonists was
GnRH antagonist in assisted reproduction: a Cochrane review
Hesham Al-Inany1 and
Mohamed Aboulghar
CONCLUSIONS: We concluded that the fixed
GnRH antagonist protocol is a short and simple
protocol with good clinical outcome, but the
lower pregnancy rate compared with the GnRH
agonist long protocol and the non-significant
difference between both protocols regarding
prevention of premature LH surge and
prevention of severe ovarian hyperstimulation
syndrome necessitates counselling subfertile
couples before recommending change from
GnRH agonist to antagonist. The clinical outcome
may be further improved by developing more flexible
antagonist regimens, taking into account individual
patient characteristics.
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Ganirelix acetate (Antagon Injection® | Organon
International) gained the U.S. Food and Drug
Administration (FDA) approval in 1999, for the
inhibition of premature ovulation in women who
are undergoing fertility treatments. The recent
findings, demonstrating the efficacy of ganirelix in
improving the pregnancy rates with the IUI
procedure, provides a new alternate option for the
treatment of women with history of premature
luteinization.
Lambalk CB, Leader A, Olivennes F, et al. Treatment with the GnRH
antagonist ganirelix prevents premature LH rises and luteinization in
stimulated intrauterine insemination: results of a double-blind, placebocontrolled, multicentre trial. Hum Reprod. 2006 Mar;21(3):632-9.
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CONCLUSION: The use of GnRH antagonist in
COS/IUI cycles improves pregnancy rate,
preventing the premature LH rise and
luteinization.
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Study of Positive and Negative Consequences
of Using GnRH
Antagonist in Intrauterine Insemination
Cycles
Shirin Ghazizadeh, M.D.1, Elham Pourmatroud, M.D.*1, Mamak Shariat, M.D.2, Masomeh Masomi,
B.Sc.1,
Conclusion: At least in CC+HMG stimulated
cycles for IUI, the occurrence of premature LH
surge could have a useful rule and GnRH antagonist
administration could be an inappropriate
intervention.
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Premature luteinization can be defined as high
progesterone to estradiol ratio on the day of
hCG administration. Premature increase in the
progesterone level may adversely affect the
endometrial receptivity or provide an
unfavorable environment in the follicles,
resulting in with adverse effects on oocyte
maturation, which would thereby affect
embryo quality. Several studies suggest that
premature rise in serum progesterone levels
reduce the pregnancy rates in in vitro fertilization
(IVF) cycles, while some other studies have
reported that the premature rise of serum
progesterone level does not adversely affect the
oocyte and embryo quality.
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J.A. Sims,
H.J. Seltman and
S.J. Muasher1
Patients were stimulated with GnRHa beginning on cycle day 2, and high
dose FSH beginning on cycle day 3. Some 85% of the cycles exhibited a
rise of serum progesterone to a peak concentration of > 1.0 ng/ml (range,
1.2–4.2 ng/ml) during cycle days 2–6. When compared to cycles with no
demonstrable progesterone rise, cycles with a rise were associated with a
significantly decreased ovarian response: more ampoules of
gonadotrophin were required (mean 26.8 versus 22.6, P < 0.05), lower
peak oestradiol concentration was reached (mean 774 pg/ml versus 1030;
P < 0.05), and fewer mature oocytes were harvested (mean 4.6 versus 7.5;
P < 0.01). Among the different pregnancy outcomes (clinical pregnancy,
no pregnancy, ongoing pregnancy, and miscarrige), there were no
significant differences detected in the early follicular progesterone
concentrations as measured by peak progesterone, progesterone area
undre the curve (days 2–6), and day of peak progesterone. The follicular
phase initiation of GnRHas can result in significant elevations of serum
progesterone in the early follicular phase, which may impair follicular
recruitment and overall ovarian response.
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Attempting to compare the rates of premature
luteinization (PL), clinical pregnancy, and cycle
cancellation in ovulation induction–intrauterine
insemination (OI-IUI) cycles with and without the
GnRH antagonist, cetrorelix, a randomizedcontrolled trial was undertaken in which patients
were randomized to one of two OI-IUI protocols.
Those in the cetrorelix arm showed a significantly
reduced rate of PL and no change in clinical
pregnancy or cycle cancellation rate, leading to the
conclusion that GnRH antagonists can decrease the
rate of PL, but appear to have no effect on
pregnancy or cycle cancellation in gonadotropin
OI-IUI cycles.
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Conclusion: This study demonstrates that a
daily dose of cetrorelix 0.2 mg is able to
prevent premature LH surge.
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Conclusion
OC pretreatment afforded flexibility in
scheduling while a reduced dose of ganirelix
avoided excessive suppression of LH. The
excellent results in this pilot study for IUI
suggest this regimen could be further
evaluated for scheduling IUI and IVF cycles.
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Results: Pregnancy rate was not significantly different in the
study group (p= 0.16), Multiple pregnancy rate and
OHSS were significantly lower in the study group (p= 0.036 and
0.026) respectively. While Spontaneous abortion
rate was not statistically different between the study and the
control group (p= 0.35).
Conclusion: Adding GnRH antagonist in IUI cycles decreased
ovarian hyperstimulation syndrome and multiple
pregnancies and didn't affect the pregnancy and miscarriage rates
in women with PCOS
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HER IUI VAKASINDA AGONİST VEYA
ANTAGONİST UYGULAYALIM MI?
PKOS
ÖNCEKİ INDUKSION DENEYİMİ
IUI MI IVF Mİ? MALİYET HESABI

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