1. Hormonal parameters used to optimize COH, Suzan tip merkezi, doc. dr. ozkan aydin leylek

4. The optimal number of retrieved oocytes following minimal or maximum ovarian stimulation in relation to benefits versus risks and side effects

6. Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients, Simon C, Hum Reprod, 1995 Considering all the patients together, significant decreases in pregnancy and implantation rates were observed when oestradiol concentrations were > 2500 pg/ml compared with patients having lower oestradiol concentrations. Our clinical results demonstrate that high serum oestradiol concentrations on the day of HCG injection in high and normal responder patients, regardless of the number of oocytes retrieved and the serum progesterone concentration, are detrimental to uterine receptivity without affecting embryo quality.

7. A scheme depicting modulation of the window of receptivity in the P4- primed uterus in response to changing estrogen levels. This scheme shows that estrogen at a low threshold level extends the window of uterine receptivity for implantation, but higher levels rapidly close this window, transforming the uterus into a refractory state.

8. Circulating levels of E 2 during the preimplantation period (days 0– 6) in patients undergoing the step-down regimen (dashed line) versus the previous failed cycle (solid line). Bars represent means ± SE., Carlos Simon, Fertility and Sterility, 1998

10. High estradiol levels and high oocyte yields are not detrimental to IVF outcome, peak E2 levels of > 3000 pg/ml on the day of hCG, Sharara FI, Fertility and Sterility, 1999

11. Value of the serum estradiol level for preventing OHSS: a retrospective case control study, Ariauna D'angelo, Fertility and Sterility, 2004

12. Evidence for different etiologies of low estradiol response to FSH: age-related accelarated luteinization of follicles or presence of ovarian autoantibodies, Luborsky JL, Human Reproduction, 2002 ● Serum hormone levels did not reflect follicular fluid hormone profiles. ● Granulosa cells of low responders expressed more LH reseptors, suggesting that follicles were more luteinized than follicles of normal responders. ● In the absence of ovarian antibodies, low responses are associated with higher age and accelarated luinization of mature follicles, rather than diminished responsiveness. ● Ovarian antibody may be an additional tool to predict and individualize treatment regimens in poor responders.

13. Impact of leuprolide acetate on luteal phase function in women undergoing COH and IUI, Duffy DA, Fertil Steril, 2006 ● A significant difference in estradiol levels (on the day of hCG administration) between cycles with a luteal phase defect (967 pg/ml±106) and without a luteal phase defect (1.422 pg/ml±83) was observed (p<0.05).

14. Peak plasma E 2 levels were lower in women with low scavenger receptor class B, type 1 RNA expression (below the 25th percentile; blue bar) compared with in women with high SR-BI RNA expression (above the 75th percentile; red bar). The mean ± SE of plasma peak E 2 levels from women with low SR-BI RNA expression (n = 9) was 43% lower (6,649.7 ± 1,030.1 pmol/L) compared with women with high SR-BI RNA expression (n = 8, 11,648.1 ± 2,456.3 pmol/L, * P<.04).Velasco. SR-BI and human female infertility. Fertil Steril 2006.

15. Receiver operating characteristics curve for prediction of pregnancy by estradiol level (area under receiver operating characteristics curve = 0.71), John y Phelps, Fertility and Sterility, 1998

16. Lowered Progesterone Levels

17. Serum P level effects on the outcome of IVF in patients with different ovarian response: an analysis of more than 10,000 cycles,1.5 ng/ml for poor responders (oocytes 20), Bei Xu, Fertility and Sterility, 2012

18. Premature progesterone rise negatively correlated with live birth rate in IVF cycles with GnRH agonist: an analysis of 2,566 cycles. Huang R, Fertility and Sterility, 2012 Huang R In GnRH agonist cycles, PPR negatively correlated with live birth rate in fresh embryo transfer cycles, although no adverse impact on frozen embryo transfer was observed, implying that PPR may have deleterious effects on endometrial receptivity.

19. Receiver operating characteristic (ROC) curve for defining optimal detrimental cutoff value for P on hCG day, P > 1.5 ng/ml and P/E2 > 0.55 affect the CPR in women undergoing cleavage- stage but not blastocyst ET, E man A, Fertility, 2011

20. Computer-assisted analysis of endometrial echogenicity. After digitation of the uterine images, several transverse cuts across a representative section of the endometrial surface were performed and gray-level analysis was displayed graphically. Endometrial echogenicity was calculated as the ratio of the extent of the submyometrial hyperechogenic transformation of the endometrium over the whole endometrial surface.

21. Plasma progesterone profile during hMG treatment (left) and after hCG administration (right). Plasma progesterone levels (mean ± SE) increased significantly in the low progesterone (P <.01) and high progesterone (P <.001) groups during hMG treatment and after hCG administration (P <.001). ∗ Differences between both groups were statistically significant (P <.01). P = progesterone, Renato Fanchin, Fertility and Sterility, 1999

22. Premature lutenization during GnRH antagonist cycles and its releationship with IVF outcome, Bosch E, Fertil Steril, 2003; Modulation of folliculogenesis and steroidogenesisi in woman by graded menotrophin administration, Filicori M, Hum Reprod, 2002 ● Serum progesterone level on the day of hCG administration (<1.2ng/ml or =1.2ng/ml) ● Premature lutenization during GnRH antagonist IVF=ET cycles is a frequent event that is associated with a lower pregnancy and implantation rates. Progesterone elevations are not related to serum LH levels and may reflect the mature granulosa cell response to high FSH exposure ● Contrary to common belief, enhanced FSH stimulated rather than LH activity appears to cause premature follicle luteinization during COS

23. Circulating P levels and OPRs in COS cycles for IVF: analysis of over 4000 cycles, E Bosch, Human Reproduction, 2010 Elevated serum P levels on the day of hCG administration is associated with reduced ongoing pregnancy rates. In particular, serum progesterone levels of >1.5ng/ml were associated with lower OPRs following IVF/ICSI cycles irrespective of the GnRH analogue used for pituitary down-regulation. Multivariate regression analysis showed that daily FSH dose, number of oocytes and estradiol values on the day of hCG administration were positively associated with progesterone levels (p<0.0001 for all). Serum P levels were significantly greater in women treated with GnRH agonist ( n=1177) versus antagonist (n=2855; 0.84±0.67 versus 0.75±0.66ng/ml; p=0.0003).

24. Progesterone rise on the day of hCG administration (premature luteinization) in IVF: an overdue update, Elnashar AM, J Assist Reprod Genet, 2010 ● Most studies used an absolute P level on the day of hCG administration as an indicator of PL, and the cutoff level differed from 0.8 to 2 ng/ml. Some authors defined PL as a P/E2 ratio of > 1. ● Several hypotheses may be considered to explain this phenomenon: elevation of follicular LH levels, serum accumulation of hCG from HMG, increased LH receptor sensitivity of the granulosa cells to FSH, or poor ovarian response with increased LH sensitivity. ● Attempts to prevent include: use low-dose hCG alone in the late COH stages, flexible antagonist protocol, use of mifepristone, aspiration of a single leading follicle, hCG administration when the levels of P exceeded 1.0 ng/ml.

25. Increased P/E2 ratio on the day of HCG administration adversely affects success of in vitro fertilization-embryo transfer in patients stimulated with gonadotropin-releasing hormone agonist and recombinant follicle-stimulating hormon,Ou yc, Taiwan J Obstet Gynecol, 2008 Premature luteinization, defined as late follicular P/E2 ratio of > 1 in long GnRHa cycles with rFSH stimulation, adversely affected ovarian responses and clinical outcomes. It seems unrelated to preovulatory luteinizing hormone (LH) elevation and LH/hCG content of gonadotropins and could be associated with poor ovarian response and the presence of dysmature follicles.

26. Impact of endogenous luteinizing hormone serum levels on P elevation on the day of hCG administration, Hugues JN, Fertil Steril,2011 ● Serum P hCG values were significantly lower following the GnRH antagonist than agonist protocol ● A positive correlation between serum P hCG and LH area under the curve or day 6 LH values was found in the GnRH agonist group and between P hCG and LH hCG levels in both GnRH analogue regimens. ● With multivariate analysis, P hCG values were positively correlated with serum estradiol levels on hCG administration day and with the total FSH dose in both GnRH analogue-treated groups. ● Additionally, the correlation between serum P hCG and LH hCG values was positive in patients treated with the GnRH agonist protocol.

28. Relationship between circulating hCG levels and premature luteinization in cycles of COH, Copperman AB, Fertil Steril, 1995 ● Higher serum levels of hCG 1.8±0.9 mIU/ml v. 1.2±0.45 mIU/ml and integrated hCG exposure are found in COH cycles with premature luteinization compared with cycles without premature luteinization ● Higher hCG levels may be due to decreased clearance of hCG from the circulation and/or the hCG content of HMG

29. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation. Serum FSH and E 2 levels and follicular development in patients with hypogonadotropic hypogonadism who were treated with increasing doses of r-FSH. Serum FSH levels increased gradually with the rising dose of FSH and follicles developed, but serum E 2 concentrations remained low. Shoham. Therapeutic window for LH. Fertil Steril 2002.

30. There is evidence to suggest that suppressed LH levels in women during ART stimulation can have negative effects. Depending on the study, adverse outcomes have been demonstrated with LH below 0.5-1.2 IU/L. LH levels < 1.2 IU/L have been reported to be associated with decreased serum estradiol, poor follicular development, decreased oocyte yield, decreased high quality embryos, and lower pregnancy rates. Below LH levels of 1IU/L, other researchers demonstrated slower follicular growth and decreased estradiol. Finally, LH levels < 0.5 IU/L have been associated with increased pregnancy loss, lower implantation rates, and lower live birth rates.

31. Randomized controlled trials demonstrating an increased estradiol level on the day of hCG with rLH (top) or hMG (bottom) as compared to rFSH alone (adapted from Hill et al., 2012).

32. Effect of androgen levels on in vitro fertilization cycles, John L. F., Fertility and Sterility, 2004

33. A relative reduction in mid-follicular LH concentrations during GnRH agonist IVF/ICSI cycles leads to lower live birth rates, R Lahoud, Human Reproduction, 2006 ● Patients with low LH concentrations were found to have a significant reduction in the late- follicular estradiol concentrations (p<0.001) ● A ratio of %50) was associated with a significant reduction in the live birth rates per embryo transfer and per cycle started (27.3 v. 19.0 %, p < 0.05 and 22.2 v. 15.8 p < 0.05, respectively)

34. Impact of “LH activity” supplementation on serum P levels during controlled ovarian stimulation: a systematic review, J.N. Hugues, Human Reprod, 2012 ● Analysis of confounding factors showed that the intensity of ovarian stimulation is the most important determining factor to explain serum progesterone elevation at the time of hCG administration ● This systematic review shows that providing LH activity supplementation in combination with FSH during ovarian stimulation does not have a consistent effect on serum progesterone concentrations at the time of hCG administration. ● The timing of LH activity administration could influence the impact on serum progesterone changes.

35. Serum LH in patients undergoing ovarian stimulation with GnRH antagonists and rFSH and its relationship with cycle outcome, Bosch E, Fertil Steril, 2005 ● The serum LH was determined on days 3, 6 and 8 of stimulation and on the day of hCG. ● Patients with high serum LH levels during stimulation showed significantly higher serum estradiol levels on the day hCG. ● No differences were observed between the number of oocytes recovered or the fertilization, implantation and PRs of the groups

36. LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels, Pezzuto A, Gynecol Endocrinol, 2010 ● It was shown that LH supplementation seems to have benefical effect on the maturity and fertilizability of oocyte ● LH-supplementation is beneficial in patients who show a significant serum LH suppression during the receptorial down- regulation. ● Lower apoptosis rate in human cumulus cells after administration of LH

37. LH role in quality of oocytes ● LH is a factor that induces final oocytes nuclear meiotic maturation, degradation of gap junctions and cumulus expansion in the follicle ● Excessive LH level may disrupt granulosa cell communication in the cumulus oophorus. ● Teresa Wiesak, Reproductive Biology, 2002

38. Elevated LH concentrations ● Prematurely allow resumption of meiotic maturation of oocytes ● Postmature oocytes, fail to become fertilized ● Produce arrested embryos ● Uneven blastomeres, excessive fragmentation ● Demise of embryo quality ● Enhanced incidence of chrosome anomalies in oocytes recovered after administration of high dose of LH and FSH 21-50 ampoules/cycle: 41% v. 6-21 ampoules/cycle: 23%

39. Does day 3 LH level predict IVF success in patients undergoing COS with GnRH analogues? Orvieto R, Fertil Steril, 2008 ● To examine whether day 3 LH level or FSH/LH ratio predict IVF outcome. ● Although LH level could not predict IVF outcome, patients undergoing COH using the GnRH antagonist or agonist protocols with FSH-LH ratios > 2 or > 3, respectively, achieved lower (PRs 27.7% v. 11.1% and 31.9% v. 8.3, respectively).

41. Serum FSH levels in coasting programmes on the hCG day and their clinical outcomes in IVF±ICSI cycles, Srisailessh Vitthala, International Journal of Endocrinology, 2012 ● LBR and CPR were significantly higher when the FSH levels on the hCG day were > 2.5 IU/L (LBR: 32.5%, p=0.045 and CPR: 36.9%, p=0.027) compared to FSH < 2.5 IU/L. ● The optimal FSH cut-off level for LBR and CPR is 5.6 IU/L on the hCG day. ● The optimal cutoff for coasting is 4 days (maximum of 4 days).

42. The important details E2 < 3000 pg/ml, E2< 75 pg/ml, E2 < 45 pg/ml P < 1.5 < 1.75 < 2.25 ng/ml, P < 0.9 ng/ml, E2/P < 1, E2/P < 0.55 1.2 IU/L< LH < 10 IU/L FSH < 10 IU/L, FSH < 5.6IU/L, FSH < 2.5 IU/L FSH/LH < 2 < 3