IUI SİKLUSLARINDA PREMATUR LUTEİNİZASYONUN ONLENMESİ

PROF.DR.MEHMET ÇOLAKOĞLUSELCUK ÜN.MERAM TIP FAK.KADIN HAST VE DOĞUM ABD

IUI-Tarihçe

İ lk yayın 1790 J ohn Hunter İ lk 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 İ lk randomize kontrollü çalışma 1984

Kerin J FP

IUI-Endikasyonlar

Hipospadias Vaginismus Retrograd ejekulasyon İmpotans Servikal faktör Subfertil erkek Açıklanamayan infertilite Endometriozis

Endikasyonlar

Penis ve vajinanın anatomik ve fonksiyonel bozuklukları

Servikal faktör Erkek infertiltesi İmmunolojik infertilite İ zah edilemeyen infertilite Husband is away from wife for long time

(work abroad) HI V negative women with processed semen

of HI V +ve husband.

IUI BAŞARISINI ETKİLEYEN FAKTÖRLER

Kadın yaşı İnfertilite süresi İnfertilite tipi Sperm kalitesi Kateter tipi ve spermlerin transfer zorluğu Matür folikül sayısı Prematur LH önlenmesi HCG gününde E2 konsantrasyonu

IUI BAŞARISI11,80

9

0,00

2,00

4,00

6,00

8,00

10,00

12,00

Siklusbaşınagebelikoranı

Siklusbaşınacanlı

doğumoranı

IUI başarısı (%)

Annual report of the French Biomedicine Agency 2005. www.agence-biomedecine.

IUI ve/veya KOH

• Doğal siklus +

Koitus

• Kontrollu ovaryen stimulasyon

+Koitus

• Doğal siklus+

IUI

• Kontrollu ovaryenstimulasyon

+IUI

KOH + IUI KadKOH + IUI Kadıınnıın Yan Yaşışı Etkili mi?Etkili mi?

Retrospektif analizRetrospektif analiz168 olgu, 469 168 olgu, 469 siklussiklus, CC+, CC+hMGhMG, , hMGhMG, FSH), FSH)

YaYaşş SiklusSiklus SaySayııssıı Gebelik (%)Gebelik (%)<40<40 210210 18184040 135135 13,313,34141 114114 7,97,94242 8484 4,84,84343 5656 1,81,84444 4545 004545 1818 00

4040--42 ya42 yaşışında klinik gebelik maliyeti KOH+IUI 30,000$ nda klinik gebelik maliyeti KOH+IUI 30,000$ IVFIVF--ET 77,000$ET 77,000$

CorsanCorsan G, 1996G, 1996

AVANTAJLAR

› Ucuz› Kısa sürede

uygulama› IVF-ET’ye bağlı

risklerden kaçınma

DEZAVANTAJLAR

› Gebelik oranı düşük› OHSS› Çoğul gebelik› Enfeksiyon › Premature LH riski

LH Surge 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

Ovaries

Hypothalamus

GnRHPituitary

LHFSH

+

24 hours

Plasma LHPulses of LH

Pulses of GnRH

Pulsatile activity of GnRH neurones

“GnRH pulse generator”

Ehrmann NEJM 2005

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

Ovulationtrigger = LH surge

occurs ~12 hr prior to ovulation

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

What is this?

Fig. 28-17 T&G

Trigger #1: 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

2525 Evidence based recommendations for practicing I UI

Grade A recommendations

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.

NICE Guidance Feb. 2004

Controlled ovarian hyperstimulation before IUI

• 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

The rationale

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.SourceDepartment of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen AB25 2ZD, UK. p.a.fowler@abdn.ac.uk

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 oestradiol secretion.

LONG AGONİST VS ANTAGONİST

PREVENTION OF PREMATURE LH SURGE

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 not significantly different.

GnRH antagonist in assisted reproduction: a Cochrane reviewHesham 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.

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, placebo-controlled, multicentre trial. Hum Reprod. 2006 Mar;21(3):632-9.

GnRH antagonist-induced inhibition of the premature LH surge increases pregnancy rates in IUI-stimulated cycles. A prospective randomized trial A. Marino, F. Coffaro, P. Scaglione, F. Sammartano,

G. Rizza

CONCLUSION: The use of GnRH antagonist in COS/IUI cycles improves pregnancy rate, preventing the premature LH rise and luteinization.

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 LHsurge could have a useful rule and GnRH antagonist administration could be an inappropriateintervention.

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.

Early follicular rise of serum progesterone concentration in response to a flare-up effect of gonadotrophin-releasing hormone

agonist impairs follicular recruitment for in-vitro fertilization

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.

Cetrorelix lowers premature luteinization rate in gonadotropin ovulation induction–intrauterine insemination cycles: a randomized-

controlled clinical trialRyan G. Steward, M.D.Inderbir Gill, M.D.Dan B. Williams, M.D.Craig A. Witz, M.D.,

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 randomized-controlled 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.

Is a lower dose of cetrorelix acetate effective for prevention of LH surge during controlled ovarian hyperstimulation? Heng-Ju Chen, Yu-Hung Lin, Bih-Chwen Hsieh, Kok-Min Seow, Jiann-Loung Hwang and Chii-Ruey Tzeng

Conclusion: This study demonstrates that a daily dose of cetrorelix 0.2 mg is able to prevent premature LH surge.

Oral contraceptive pretreatment and half dose of ganirelix does not excessively suppress LH and may be an excellent choice for

scheduling IUI cycles David R. Meldrum, Denise L. Cassidenti, Gregory F. Rosen, Bill Yee and Arthur L. Wisot

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.

Adding GnRH Antagonist In IUI Cycles Decreased The Complications And

Didn't Affect The Outcome In Women With PCOSFatma aletaibi M.Da, Walid El-Sherbiny M.Db, Ahmed Nasr M.Db

a Consultant of Obstetrics and Gynecology , Soliman Fakeih Hospital, Saudi Arabia.b Assistant Professor of Obstetrics and Gynecology , Department of Obstetrics and Gynecology, Faculty of

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

SONUÇ

HER IUI VAKASINDA AGONİST VEYA ANTAGONİST UYGULAYALIM MI?

PKOS ÖNCEKİ INDUKSION DENEYİMİ IUI MI IVF Mİ? MALİYET HESABI