D. de Ziegler, C. Villette, C. Gauché, P. Santulli, C. Chapron, V. Gayet
Université Paris Descartes – Hôpital Cochin, Paris France.
Introduction: prorgesterone for LPS
Practically from incept of ART, it has been ruled that luteal phase support (LPS) is necessary for optimizing outcome. This stems from the fact that the normal stimulation of the corpus luteum exerted by the pituitary – by a pulsatile production of LH – is impaired in ART through combined effects of the various treatments used. For LPS, exogenous progesterone is started on the day of oocyte retrieval, or a little later. The alternate option is to administer hCG for sustaining endogenous progesterone production. The latter is generally abandoned however due to a markedly increased risk of ovarian hyper-stimulation syndrome (OHSS) caused by hCG.
Hazard and risk
Hazards are inherent to any activity or operation. In mountain climbing, the hazard is height. The risk associated with this risk is to slip. While risks can be mitigated, hazards remain and need to be dealt with. In mountain climbing, a rope will mitigate the risk of slipping with possible consequences that are directly derived from the prevailing hazard, height.
When early developing embryos are exposed to hormonal treatments, as for LPS, the prevailing hazard is the possibility that hormones impact on the expression of genes, i.e. causing epigenetic alterations. The risks that may stem from this are not know, but the seriousness of the consequences is obvious. An example of epigenetic alterations caused by hormonal treatment is the consequence of DES exposure of female embryos through maternal treatment with DES for preventing miscarriages.
Progesterone for LPS: Routes, doses and concentrations differ.
Originally, progesterone was administered by injections. These were in oil-base solutions due to the highly insoluble characteristics of progesterone. The doses used varied from 25 to 100mg, 1-2 times a day. Oral and transdermal administration of progesterone being not possible due to poor bioavailability, the vaginal route was the sole alternate option. The doses used varied even more, ranging from 12mg (ring), to 90mg(Crinone®), to 300mg (Endometrin®), to 600mg (Utrogestan®, Prometrium®, Cyclogest®). It is thus difficult to precisely determine the amounts of progesterone that are ultimately absorbed and ultimately reach the uterus after vaginal administration or progesterone.
The quest for minimal effective doses
Today, a new progesterone preparation developed in aqueous solution, Prolutex®, has been tested for efficacy on the endometrium in absence of endogenous progesterone. This trial demonstrated equal efficacy of 25mg/day – the amount produced in the luteal phase of the menstrual cycle – and 50mg/day, leading to logically adopt the lower dose of 25mg/day for the phase III trial and definitive use of Prolutex®. This product is therefore the only one whose efficacy in LPS was tested at physiological amounts reaching the developing embryo.
Conclusion
We are at a loss for determining the exact risks that are possibly caused by exposing early developing embryos to excessive amounts of progesterone – delivered and/or concentrating in the uterus. We know however the importance of the epigenetic hazards that may ensue from such exposure. In these conditions therefore, utmost caution should be applied for shunning excessive hormonal exposure of the developing embryos as much as possible.
Figure 1
Fig. 1. Hazard and risks of excessive progesterone (P4) exposure
A hazard is inherent to the nature of any business. In mountain climbing, the hazard is height. For P4 treatment in a woman attempting to conceive, the hazard is the possibility of epigenetic alterations in the developing embryo. Risks ensue from hazard. In mountain climbing the risk is to slip. In hormonal treatments given to women trying to conceive, the risks that may unravel from the epigenetic hazard are still unknown. Yet knowing the nature of the hazard should lead the greatest precaution. In case of hormonal treatment, precaution calls for using the minimum effective dose.
Figure 2
