Definition of the luteal phase status in ART cycles: can it be described as Luteal phase dysfunction, or luteal phase insufficiency?

I would not readily support the use of ‘luteal phase insufficiency’ for describing what happens in COS and would prefer ‘luteal phase dysfunction’, as it more humbly states what we are dealing with.

Actually, the little we know about it.  On the pragmatical side, LPS has been provided from the heydays of IVF, but for all sorts of purported mechanisms.  Some – i.e. the early hypothesis incriminating the missing granulosa cells as a result of follicular aspiration – were proven wrong.  Others – i.e. an out of balance E2/P4 ratio – are totally out of synchrony with our current thinking.

What remain are some knowledge that some sort of luteal dysfunction exists and the concept that LPS has been proven effective.  Indeed, the only stronghold in this domain is the trove of clinical evidence indicating that LPS is necessary until at least the positive pregnancy test.  But even that – although purported by all as the Holly Grail – holds its own hollow points as well.

Indeed, the latest Meta-analysis (Cochrane 2011) reporting that LPS provides better results than no treatment also indicated that oral P4 – itself incapable of inducing predecidual changes in the endometrium – was as effective as vaginal P4 (?).  Such findings attributed to statistical flukes are mind-boggling nonetheless.

What might be the mechanism for such a need?

As for the mechanism responsible for the need for LPS, we start understanding a little more even if confusion still looms large.  The needs for LPS 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 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 preg test for example) being harmless support this putative mechanism.

Hence in my eyes, the term of ‘luteal phase dysfunction’ encompasses a broader spectrum of alterations, inducing dys-synchrony, and better accommodates the fact that actual P4 production may at times be supra normal.

What is the best model to test the role of progesterone in this contents?

The best model for testing LPS regimens is still the donor egg model, when no endogenous P4 production exists.  In the donor egg model, endometrial receptivity still surpasses all other conditions.

The message here is double: (i) E2 and P4 alone suffice for priming endometrial receptivity; (ii) everything else that is produced by the ovaries – possibly in excessive amounts in COS – at best does nothing on receptivity or, may harm.  The good results of the donor-egg model also indicate that all the alterations encountered in the donor egg model are not reflective of poor endometrial receptivity (as it is the best model).

Actually, some differences exist between the endometrial findings in the mid-luteal phase of donor egg cycles and the menstrual cycle.  The most striking of these differences is the lagging in glandular changes that amount to at least 2 days.  Many have also reported some degree of stromal advance.  The 2 together result therefore in the so-called glandular-stromal dyssynchrony.  These 2 changes actually reproduce some of the findings made in COS and incriminated as causing the altered receptivity.  Our views have evolved from our article of 18 years ago, opening to a more complex picture.

The ultimate model for our treatments – the donor-egg E2 and P4 cycles – provides the best implantation possible, but reproduces what we held as responsible for the altered receptivity in COS.

In my eyes, the OMIC studies have not provided much help so far.  Indeed, investigators have concentrated on comparing day-7 samples obtained in COS to findings made at a similar timing in the menstrual cycle.  They propose that the differences seen are instrumental in altering endometrial receptivity.  I’m not sure.  They may be pursuing some red hearing, as some of those differences may actually represent changes in the glandular epithelium – very active at this stage of the luteal phase – but not necessarily harming receptivity (of the donor egg model).

Further OMIC efforts should actually compare the whole changes occurring in the endometrium (follicular and luteal phase), not just focus on the so-called window of receptivity.  We (I mean others) precisely did the same mistake with luteal phase defect (hence, not a good term).  We (others) focused at the time of the biopsy, while the problem stems from the follicular phase (poor follicle – poor luteal phase).

When progesterone needs to be initiated?

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, we believe that a novel factor has entered the game since we published that article 18 years ago (!!!), which compounds the issue.  It is the emerging concept that certain pathologies such as endometriosis are associated with an inflammation-related resistance to P4 (L. Giudice).  This phenomenon appears to be ovarian-function driven, with a situation that normalizes itself upon stopping ovarian function with either GnRH-a or OC (see article by I. Faser).  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.

What happens to the luteal phase after ovulation is triggered with GnRH-a?

There is another issue that's most puzzling and of increased interest.  What happens to the luteal phase after ovulation is triggered with GnRH-a?  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.

Why would IM P4 work and vaginal P4 not, when uterine tissue concentrations are higher with vaginal P4? I discussed in a recent article on IVM in PCOS, which came out this month in FS.   I have a hypothesis for injectable being superior to vag. There.

To sum up, the situation of luteal dysfunction in COS as it stands today tells us:

• The donor-egg E2 and P4 model remains the best possible reference for endometrial receptivity.
• Some degree of luteal dysfunction exists in COS, probably because of improper support of CL by LH.
• P4 overall improves ART’s results, but is not a ‘cure-all remedy’.
• In endometriosis and possibly other conditions (adenomyosis? PCOS?), there is documented state of resistance to P4 in the endometrium, probably inflammation-related.  Ovarian suppression by GnRH-a or OC appears to correct this situation.
• Novel breakthroughs in cryopreservation open new possibility in case of repeated implantation failures by allowing postponing transfers and conducting them in perfect E2 and P4 cycles.

Dominique de Ziegler, MD
Professor and Head
Div. Reprod. Endocr. and Infertility, Université Paris Descartes - Hôp. Cochin, 53 Ave de l'Observatoire, 75014 Paris, France

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