Levent M. SENTURK, M.D., Professor in Ob&Gyn Istanbul University Cerrahpasa School of Medicine Dept. of Ob&Gyn, Division of Reproductive Endocrinology,

Levent M. SENTURKLevent M. SENTURK, , M.D.,M.D., Professor in Ob&GynProfessor in Ob&Gyn

Istanbul University Cerrahpasa School of MedicineIstanbul University Cerrahpasa School of MedicineDept. of Ob&Gyn, Division of Reproductive Endocrinology, Dept. of Ob&Gyn, Division of Reproductive Endocrinology,

IVF UnitIVF Unit

Should we use Should we use estrogensestrogens in luteal phase support? in luteal phase support?

Implantation• Implantation window is the most critical period

of time in human reproduction.

• Human embryo at blastocyst stage and endometrium in secretory phase come to contact with each other

•Apposition•Attachment•Invasion

Luteal phase support

• The estimated onset of placental steroidogenesis (the luteoplacental shift) occurs during the 5th gestational week, as calculated by the patients’ last menses. Scott et al., 1991

• Stimulated IVF cycles are associated with a defective luteal phase in almost all patients.

Ubaldi et al., 1997; Macklon and

Fauser, 2000; Kolibianakis et al., 2003

Luteal phase support‘‘...although it can be shown statistically that aspiration

of follicles may be associated with a decreased luteal

function in both oestrogen and progesterone

steroidogenesis, we do not believe that this is of

clinical significance in most patients...’’

‘‘...once more, it should be emphasized that the average

patient following in vitro fertilization will not, in our

experience, need supplementation of the luteal

phase...’’Georgeanna Seegar Jones, 1982(Norfolk IVF)

Luteal phase support• Use of GnRH agonist causes the suppression of

pituitary LH secretion for as long as 10 days (2 to 3 wks) after the last dose of agonist.

• Without this LH signal, the corpus luteum may be dysfunctional, and subsequent progesterone and estrogen secretion may be abnormal.

• Without proper progesterone or estrogen stimulation, endometrial receptivity may be compromised, leading to decreased implantation and decreased pregnancy rates.

Luteal phase support• In the luteal phase of an IVF cycle, serum E2 and P

often drop to low levels unless hormonal support is provided, resulting in reduced implantation and pregnancy rates Hutchinson-Williams, et al, 1989

• This defect in the luteal phase is more pronounced in GnRH-agonist long protocols compared with short protocols and is present even after an early cessation of its administration

Devreker, et al., 1996; Beckers, et al., 2000

Luteal phase support• It is well accepted that luteal phase supplementation is

crucial from the time of clearance of exogenous hCG given for final oocyte maturation until the appearance of endogenous hCG during the early phases of implantation

Nyboe Andersen, et al., 2002

• Supplementation of the luteal phase with P in IVF cycles is the most commonly used approach, whereas support with hCG is associated with an increased risk of OHSS

Daya and Gunby, 2004

• The benefit of additional luteal The benefit of additional luteal supplementationsupplementation with Ewith E22 is is, however, , however,

controversial.controversial.

Luteal phase support – E2

• The role of E2 in the follicular phase of the menstrual cycle is well documented.

• E2 is essential for endometrial priming, also responsible for proliferation of uterine surface epithelium, glands, stroma, and blood vessels.

• The role of E2 in the luteal phase, including the preparation of the endometrium for embryo implantation, remains unclear, and its depletion in the human luteal phase does not appear to adversely affect the morphological developmental capacity of the endometrium Younis, et al., 1994

Luteal phase support – E2• The decline in late luteal E2 in unsuccessful cycles

raised speculations that peri-implantation endometrial development may be compromised

Smitz, et al., 1988

• Magnitude of the decline in serum E2 concentrations, measured by the ratio of peak E2 (on the day of hCG

administration) to midluteal E2 (10 days after hCG administration), was found to be predictive of IVF success.

Peak E2

_________________ 5

Midluteal E2

resulted in significantly lower implantation and ongoing pregnancy rates.

Sharara and McClamrock, 1999

Progesterone vs. HCGModerate-severe OHSS / ET Daya and Gunby, 2004Daya and Gunby, 2004

OR= 0.46 OR= 0.46 (0.26-0.81)(0.26-0.81)

Progesterone + E vs. PLBR / ET

Daya and Gunby, 2004Daya and Gunby, 2004

OR= 0.89 OR= 0.89 (0.34-2.32)(0.34-2.32)

Progesterone + E vs. P OPR / ET


OR= 0.89 OR= 0.89 (0.34-2.32)(0.34-2.32)

Progesterone + E vs. PCPR / ET


OR= 0.89 OR= 0.89 (0.43-1.84)(0.43-1.84)

Gelbaya, Gelbaya, et al., et al., 2008, 2008, in pressin press

• An electronic search was conducted targeting all reports published between January 1960 and March 2007

• 10 RCTs met the criteria for inclusion in the meta-analysis.

Fertil Steril, 2008, in pressFertil Steril, 2008, in press

GnRH-a, long protocol • Smitz, et al., 1993• Lewin, et al., 1994• Farhi, et al., 2000• Tay, et al., 2003• Gorkemli, et al., 2004• Lukaszuk, et al., 2005

GnRH antagonist• Fatemi, et al., 2006



GnRH-a, short protocol• Farhi, et al., 2000

GnRH-a or GnRH antagonist• Engmann, et al., 2005• Pouly, et al., 2005• Serna, et al., 2008



• 10 RCTs• The sample size varied from 63 to 666 cycles• A total of 2280 ET cycles

• E2 was administered orally in 7 studies• Smitz, et al., 1993• Lewin, et al., 1994• Farhi, et al., 2000• Tay, et al., 2003• Lukaszuk, et al., 2005• Pouly, et al., 2005• Fatemi, et al., 2006



• E2 was administered transdermally in two studies• Gorkemli, et al., 2004• Serna, et al., 2008

• and vaginally in one study• Engmann, et al., 2005 ( 2008)



• P was given vaginally in the majority of the studies,• by IM injection in two trials

• Lewin, et al., 1994

• Engmann, et al., 2005 (2008)• both vaginal and IM route

• Farhi, et al., 2000• by vaginal or oral route

• Pouly, et al., 2005

• The duration of treatment and the doses of E2 and/or P varied between studies



• All studies that were included in the meta-analysis showed no difference between groups regarding the population characteristics such as

• age,• cause and duration of infertility, • total dose of gonadotropins,• number of embryos transferred



• Three studies reported significantly improved

outcomes after administration of combined E2 and P,

including higher

• PR per ET,

• PR per cycle,

• CP and OP rates per ET,

• and implantation rate

• The remaining trials showed nonsignificant

differences between the compared arms for all

outcome measures




Smitz, Smitz, et al., et al., 19931993

Lewin, Lewin, et al., et al., 19941994

Farhi, Farhi, et al., et al., 20002000

Tay, Tay, et al., et al., 20032003

Gorkemli, Gorkemli, et et al., al., 20042004

Lukaszuk, Lukaszuk, et et al., al., 20052005


Lukaszuk, Lukaszuk, et al., et al., 20052005







Engmann, et al., 2005

Pouly, et al., 2005

Serna, et al., 2008

Fatemi, et al., 2006









Engmann, Engmann, et al., et al., 20082008


n=84n=84 n=82n=82

• long GnRH agonist suppression / GnRH antagonist /microdose GnRH agonist protocol• Vaginal estrace 2mgx2/d

n=54n=54 n=57n=57

• Although NO beneficial effect of E2 supplementation in the luteal phase of IVF cycles was shown, the up-to-date evidence remains rather scarce.

• A large, well-designed, multicenter RCT that would further clarify

• the role of luteal E2 supplementation in IVF and

• would also investigate the optimal regimen

(dose and route)


CONCLUSIONCONCLUSION

Thank you...

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Levent M. SENTURK, M.D., Professor in Ob&Gyn Istanbul University Cerrahpasa School of Medicine Dept. of Ob&Gyn, Division of Reproductive Endocrinology,