Ferring Educational Programm

The program below presented to raise the controversies and to raise a debate on LPS in ART cycles, striving to reach a consensus based on EBM

The below mentioned experts participating in the symposium:
Baris Ata, Turkey
Barr Pedro, Spain
Daya Salim , Canada
De Ziegler Dominique , France
Grudzinskas Gedis, UK
Roy Homburg, Israel
Leong Milton, Hong Kong
Shoham Zeev, Israel
Silber Sherman , USA
Tan Seang Lin , Canada
Weissman Ariel , Israel

The session organized was due to review by experts theneed, duration and formulation of progesterone during the luteal phase in ART program.

Introduction

In his seminal and historical description of endocrinology in the mid nineteen-century, Claude Bernard envisioned that hormones exert a regulatory control over their target organs. The signals mediated by E2 and progesterone indeed trigger sets of effects that are defined and pre-organized in the target organ, the endometrium itself. The secretory transformation of the endometrium and the privileged moment of endometrial receptivity to embryo implantation are part of a sequence of endometrial effects triggered by hormonal signals. Donor egg ART (DE-ART) taught us that the endometrium becomes receptive to embryo implantation after 3-4 days of progesterone exposure. Remarkably, higher serum or uterine tissue concentrations of progesterone alter neither the quality, nor the time-course of endometrial receptivity. The progesterone signal fostering endometrial receptivity simply controls the timing of the window of receptivity.

Dr. Pedro Barri, reviewed the needs of luteal support. Dr. Barri hypopthesied that the supraphysiological steroid concentrations and consequent LH suppression which are common in IVF cycles, causes disruptions to the luteal phase leading to inadequate endometrial development and asynchrony in the embryo – endometrium dialogue. Prof. Barri mentioned that although there is a rapid recovery of the pituitary in GnRh antagonists cycles luteal support remains mandatory in the majority of IVF cycles.

Dr. Ariel Weissman, suggested that the high steroid levels have a negative feedback on the hypothalamic-pituitary axis, resulting in suppression of LH secretion, that leads to a drop in serum E2 and P to very low levels during the mid-luteal phase, resulting in reduced implantation and pregnancy rates.

Dr. Dominique De Ziegler, raised the hypothesis that the mechanisms responsible for the need for are indeed rooted in the alterations in the luteal support normally exerted by the pituitary in the form of pulsatile LH production. This is impaired in Controlled Ovarian Stimulation (COS) as a results of: (i) the extensive use of GnRH analogues (antagonists and agonists); (ii) the excessive ovarian response (E2 and other non-steroidal factors) and; (iii) possible direct effects of hCG used for triggering the final stage of ovulation. According to this mechanism of COS-related alteration in P4 production, luteal support would become normal under the influence of hCG as soon as pregnancy is established. The available data on early discontinuation of LPS (on the day of the positive pregnancy test for example) being harmless support this putative mechanism.

Dr. Dominique De Ziegler spoke about the Luteal phase after ovulation is triggered with GnRH-agonist. He mentioned that the endometrium is screwed up and conventional regimens (vag. P4 and E2) - tested in donor egg - don't work. Yet, IM P4 works as recently reported and described as 'aggressive LPS' by Engman et al.

Stimulation protocols

Dr. Milton Leong raise the following questions regarding the various drugs administered.

• Does FSH stimulation by different ways lead to different luteal phase responses?
• Is there is difference between down regulation with GnRH agonists and no down regulation but using GnRH antagonists?
• Does LH trigger vary the luteal phase? Differences between HCG and GnRHa?

Triggering final stage of oocyte maturation with GnRH agonist
Dr. Pedro Barri mentioned that accepting the fact that progesterone still is the gold standard for the luteal support of the majority of IVF cycles, the question nowadays is to tailor new protocols for cycles in which triggering has been carried out with a bolus of GnRH agonist, clinical approach that is becoming more and more popular in the recent years not only for patients at high risk of OHSS but also for postponing embryo transfer for an artificial cycle.

Further to the above Dr. SL Tan suggested that the LH surge induced by GnRH agonist lasts shorter than the endogenous LH surge. Compared to the conventional hCG trigger, this short-live LH surge provides a limited luteinizing stimulus for granulose cells. This prevent excessive VEGF formation and development of OHSS in women at risk. Although all oocytes and embryo development are with no difference implantation rate are decreased. This is due to luteolytic effects of the agonist trigger.

LPS after final triggering with GnRH agonist
Dr. Dominique De Ziegler raise the discussion about why IM P4 work and vaginal P4 not, when uterine tissue concentrations are higher with vaginal P4? He hypothesis that after al the benefits of IM over vaginal progesterone seen after GnRH-agonist trigger arrears to be depended on circulation levels of progesterone, and not uterine tissue concentration.

Preparation for LPS
Dr. Roy Homburg set the seen for the discussion. He brought forward the preparations in use for luteal phase support are progesterone, hCG and GnRH agonist. Progesterone, the most popular, comes in several forms: oral tablets, vaginal gel, vaginal pessaries and in a slow-release ring, intra-muscular and sub-cutaneous injections. Oral progesterone is mostly ineffective for luteal phase support. Vaginal gel (x1/day) and vaginal pessaries (x2-3/day) are equally effective. A slow-release vaginal ring, changed once a week, produces similar clinical pregnancy rates as vaginal gel. Intra-muscular injections are effective but have uncomfortable side effects. A sub-cutaneous progesterone injection has now successfully completed trials. Injections of hCG are effective but produce an increased incidence of OHSS. A single administration of GnRH agonist in the mid-luteal phase seems to produce a greater probability of live birth.

hCG
Dr. Pedro Barri mentioned that Luteal supplementation with human chorionic gonadotropin (HCG) has proven efficient in overcoming luteal phase defects, however this treatment is frequently associated with an increased risk of ovarian hyperstimulation syndrome (OHSS) for this reason the most widely used form of luteal support is progesterone.

Dr. Gedis Grudzinskas suggested that the growing database on the use of human derived or recombinant hCG for luteal phase support in women treated with the antagonist-agonist trigger protocol has indicated that the requirements of safety efficacy and high patient acceptance are being achieved. Repeated low dose hCG administration is effective and it is likely that a novel hCG formulation with an extended half-life will be available soon providing hCG bioactivity for 7-10 days. Unanswered questions include whether additional progesterone should also be used and if so when in the context of “fresh” derived embryos for transfer and equally whether hCG should be added when medications are used for frozen thawed embryo transfers. It is imperative that well designed trials are conducted to answer these questions so that we do put women at risk of losing the clear benefits of added progesterone such as higher implantation rates, and lower rates of miscarriage and preterm labour.

Progesterone formulation (Vaginal, IM, Oral and combination of the drugs)
A lot of controversies was raised when it reach the point of which formulation to use. It is clear that the majority is using vaginal progesterone suppositories or gel, some use proteome IM, few use oral progesterone and the minority are using oral progesterone.

Dr. Pedro Barri mentioned that natural progesterone administered by the vaginal route has been the most commonly used protocol for luteal support. Recent developments will allow to use new subcutaneous preparations that will improve patients’ compliance.

Vaginal vs. IM progesterone
Dr Sherman Silber, critically reviewed the literature which certainly favored in the past the equivalence of vaginal vs. IM progesterone. However, most of the data comes from earlier studies supported by companies that make vaginal progesterone platforms, and so there is an inherent bias. Dr. Silbermentioned that in fact no study attempts to show a superiority of vaginal progesterone, just an "equivalence", so that IM is still in a sense considered by all to be the "gold standard".
Dr. Silber mentioned that a very large study, uncontaminated by drug company support, was just completed by the Shady Grove Clinic in Washington DC in the United States, by Dr. Jeffrey McKeeby. It involved only frozen embryo transfers because that is the only situation in which the implanting embryo is totally dependent on exogenous progesterone. The live birth rate for IM progesterone was 45.3 per cent, and for vaginal progesterone was 36.1 per cent. Dr McKeeby was actually sad and apologetic about these findings, but based on them, Shady Grove, the largest IVF center in the United States has decided it will only use IM rather than vaginal progesterone. A similar finding was reported by Dr Eve Feinberg in Fertil and Steril in January this year, from the second largest IVF program in the United States, The Fertility Centers of Illinois. A similar result was reported in Fertil and Steril in December of last year by Kaser. Furthermore, all of the most successful and high profile IVF programs in the United States have come to the same conclusion, including NYU in New York, and The Colorado IVF Center in Denver, as well as ours in St Louis. This is totally against what we all wanted to believe, but most of the highly successful programs in the United States prefer IM to vaginal progesterone. One constant and simple observation supporting this conclusion, aside from the recent controlled studies Dr. Silber already alluded to above, is the phenomenon of menstrual bleeding before the negative pregnancy test, a sure sign that luteal phase support was inadequate.

Dose of progesterone and for how long?
Dr. Dominique De Ziegler emphasis that the secretary transformation of the endometrium depend on the duration of exposure and not the actual levels. Practically therefore, the priming of endometrial receptivity to embryo implantation depends on the duration of exposure to progesterone rather than actual blood or uterine tissue levels. Controlling the proper timing of progesterone exposure is therefore of paramount importance for optimizing pregnancy chances in ART and donor eggs. Endometrial window of receptivity, is a short-lived condition occurring on the 3-4th day of progesterone exposure. This is evidenced by the fact that the route of progesterone administration does not modify the endometrial changes and the timing of the window of implantation. In addition, contrary to E2, progesterone carries no risk of its own, notably no cardio-vascular or venous-thrombo-embolic (VTE) risk.
Dr. Barri mentioned that that a growing body of evidence is supporting the concept and raise concern that progesterone supplementation might be necessary for luteal support but could be unnecessary for early pregnancy. The challenge today is not only to reduce the duration of progesterone treatment in early pregnancy but probably clarify its use for luteal support in terms of products, dose and route of administration.

When progesterone needs to be initiated?
Dr. Dominique De Ziegler stated that the timing for starting luteal support has been a matter for debates. The fear that an early onset might harm was grounded on the hypothesis that it might artificially advance the closure of the window of receptivity. Yet, starting vaginal P4 on the day of retrieval – it gives higher uterine tissue concentrations than IM – was proven to not be harmful, as reported by Levine HL. There are no reasons to suspect differences for IM P4. Furthermore, Dr. DeZiegler believed that a novel factor has entered the game like certain pathologies such as endometriosis are associated with an inflammation-related resistance to P4. This phenomenon appears to be ovarian-function driven, with a situation that normalizes itself upon stopping ovarian function with either GnRH-a or oral contraception (OC). In case of endometriosis, Surrey et al. reported normal pregnancy rates following 3-6 month suppression of ovarian function with Lupron and we reported the same with 6-8 weeks of OC pill.

LPS with GnRH agonist
Dr. Pedro Barri mentioned that we know that in adverted GnRH agonist administration in the luteal phase does not interfere with the evolution of a pregnancy after ART. For these reasons some authors suggested that GnRH agonist administration in the luteal phase to enhance implantation. Recent studies and meta-analyses have shown that the use of GnRH for luteal support could improve the pregnancy rate obtained. Nevertheless considering the heterogeneity of the different trials, we relieve that it is too premature to recommend the use of GnRH agonist for luteal support. Additional randomized and controlled trials are mandatory to obtain evidence-based recommendations.

The needs of estrogen to support the luteal phase
Dr. Ariel Weissman discussed the topic of Estrogens supplementation during the luteal phase. Dr. Weissman mentioned that compared to P, relatively few studies have been conducted on E2 supplementation for luteal support, and conflicting results were reported. Four meta-analyses have been recently published on this subject, and all came to the same conclusion that there is no clear benefit in adding E2 to the luteal support regimens. This conclusion, however, should be evaluated with caution, since most studies included in the analyses suffer from a large degree of heterogeneity. For example, in the study of Farhi et al. ( Fertility and sterility 2000;73:761), only high responder patients were included, and only in those stimulated on a long GnRH agonist protocol the addition of oral E2 was found beneficial. A significant increase in serum E2 levels was demonstrated in E2 treated patients. In the study by Lukaszuk et al.( Fertility and sterility 2005;83:1372), several oral doses of E2 were used with an increasing beneficial effect of E2 supplementation in a dose-dependent manner. In the study by Engmann et al.( Fertility and sterility 2008;89:554), the vaginal route was used and very high serum E2 levels were achieved, which could be detrimental. In the study of Lewin et al. ( Fertility and sterility 1994;62:121) a low dose of oral E2 was used, that did not result in different serum E2 levels in treated and non-treated patients. Because of considerable differences in E2 doses, routes of administration, timing of treatment, patient populations and outcome variables reported, it is very difficult to include many of the eligible studies in meta-analyses in a comprehensive manner without causing significant bias. In addition, live birth rate as the major clinical determinant of success has only been reported in very few cycles, and the number of patients analyzed in eligible trials might be far below the sample size required to prove a clinically significant difference. Therefore, the validity of the conclusions of the meta-analyses should be questioned. In addition, hormone treatment during the luteal phase is conducted empirically and is rarely individualized. Lack of clearly defined morphologic or hormonal criteria that relate to appropriate endometrial preparation make the evaluation even more complex. There is a certain need for further research in order to better understand the role of E2 during the luteal phase of ART cycles and to define patient-specific treatment criteria and goals. Only then properly designed RCTs can be carried out that will finally tell us whether the inclusion of E2 in luteal support protocols can increase the probability of pregnancy and live birth in ART.

Active management of the luteal phase
Dr. Baris Ata presented a combined drug formulation to support the luteal phase. Steroids, aspirin, estrogens and GnRH analogues have been suggested as useful adjuncts to progesterone. Effectiveness of these agents is controversial when they are given to the general patient population. However, luteal phase characteristics can be different among patients and a patient tailored luteal support protocol may improve clinical outcome. Identification of patients with different luteal support needs should be considered on individual basis.

Clinical investigation: the use of drugs for LPS based on surveys done on IVF-Worldwide website
Dr. Zeev Shoham presented two different web surveys which were performed through IVF-Worldwide website. In the first one, results were obtained from 84 IVF units from 35 countries representing 51,155 treated IVF cycles, and a second survey performed 3 years latter in which 408 centers from 82 countries participated, representing 284,600 IVF cycles. In both surveys no consistency were noted. Despite the lack of evidence to support continuation of LPS beyond the day a clinical pregnancy is established, the two surveys show that in clinical practice almost two-thirds of the cycles receive luteal phase supplementation until 10 to 12 weeks of gestation. Among the explanations for such a practice is the increased risk for vaginal bleeding following the discontinuation of progesterone and the emotional stress this causes patients. Although this argument is reasonable, even without firm evidence that continuation of progesterone treatment beyond the day of a positive β-hCG or the day fetal heart pulsations are detected is advantageous in terms of ongoing pregnancy rates, it is still not clear why in almost 30% of the cycles women should tolerate a prolonged treatment with daily IM injections (since in some centers this is the common way to LPS), when the alternative vaginal route has comparable pregnancy rates.

Figure 3: Type of progesterone use (IVF-Worldwide survey, data sample is 284,600 cycles reported by 408 IVF centers).

Figure 4: Duration of progesterone support if the patient conceived (IVF-Worldwide survey, data sample is 284,600 cycles reported by 408 IVF centers).