D. de Ziegler, C. Villette, A. Ambrosetti, C. Gauché, P. Santulli, C. Chapron
Université Paris Descartes – Hôpital Cochin, Paris France.
Regulatory and permissive modes of hormonal control
We were taught to expect that hormonal effects in general and those of reproductive hormones – E2 and progesterone – in particular obey to direct dose-effect rules. These views on hormonal effects emanate from Claude Bernard’s views of endocrinology in the mid 19th century. In this seminal description, hormones were seen as exerting a regulatory control on their target organs. The emblematic example of this is given by the insulin-and-glucose dose-effect relationship. In reproductive endocrinology however, we reported (Fig-1)that the actions of E2 and progesterone on their target organ – primarily, the uterus – follow a different mode of interaction identified as permissive control (Fig-1). In the permissive control mode, hormones – progesterone notably – exert effects on their target organs – the uterus for progesterone – that are pre-organized in that organ rather than modulated (‘controlled’) by hormone levels. Progesterone for example induces the predecidual transformation of the endometrium following a logic that is time- rather than blood-level dependent. The window of receptivity defined by a number of days of progesterone exposure, is an emblematic example of this.
Options for progesterone administration
Progesterone has been offered in oil-base preparations for IM injections from times that long predated the advent of ART when it was approved for treating abortion threats. Logically, these products were the first preparations used for luteal phase support (LPS) in ART. Progesterone cannot be administered orally or transdermally however, due to a high degree of metabolism during the firstliver pass and poor skin absorption, respectively. Hence, the vaginal route stood as the only remaining alternative to the painful IM injections and their complications. Unexpectedly, vaginal administration was associated with some degree of direct vagina-touterus transport or first uterine pass effect (FUPE) (Fig-2) (Fig-3).
Doses of progesterone used in IM injections and vaginal administration
IM progesterone has been used for LPS in doses ranging from 25 to 100mg, once to twice a day. No study reported any difference in efficacy – endometrial effects or PRs following fresh or donor-egg ET – between these doses. In spite of this, it is interesting if not intriguing to note that no regulatory agency ever insisted on knowing the minimum-effective-dose of progesterone administered for LPS, as it is generally the case for any drug put on the market. As neither oral nor transdermal progesterone are an option foe LPS, the vaginal route stood as the only possible alternative to IM administration. Vaginal administration of progesterone soon proved to be effective in spite of the relatively low – sub-physiological – levels of serum progesterone achieved. Today, vaginal progesterone preparations are widely used for LPS in ART in spite of the fact that concerns about compliance exist due to personal (or cultural) dislike for the vaginal route of administration. As for IM, the doses used vary greatly however, ranging from 12 mg/day (vaginal ring) to 600mg/day (200mg micronized capsules TID). In the case of vaginal administration of progesterone too, there has not been any evidence of dose effect relationship. In spite of this, no minimum effective dose was ever determined, which constitutes a very dysfunctional void in today’s era of concern for the epigenetic hazard that accompanies the un-physiological hormonal exposure of early developing embryos (bitterly learned with DES
New SC progesterone (25mg/day)
The hydrophobic characteristics of progesterone have precluded the development of aqueous progesterone preparations in the past. An invention made by IBSA pharmaceuticals upended this problematic however. Coupling progesterone to a starch residue – cyclodextrin – allowed developing an aqueous preparation of progesterone. The aqueous progesterone preparation was tested in hormone-deprived women using a donor-egg like treatment scheme for its ability to trigger the predecidual transformation of an estrogen-primed endometrium. In this model, 25mg and 50mg were found equivalent, both triggering predecidual changes in the endometrium that mimicked the findings made in the luteal phase of the natural cycle. This logically led to retain the lower dose of 25mg – a dose equal to the endogenous production in the natural cycle – as primary therapeutic dose for LPS in ART. The new SC progesterone preparation is therefore the first LPS preparation developed with concernsfor limiting the hormonal exposure and shadowing the conditions prevailing in the menstrual cycle.
Conclusion
Contrary to the insulin-glucose relationship, progesterone exerts a control on its target organ – the uterus – that follows a permissive, not a regulatory mode. This explains that the window of receptivity is controlled by the duration of exposure to progesterone, not by the actual levels of hormone. This latter fact is emblematic for the increased complexity of the dose-effect relationship of progesterone’s effects on the endometrium. Yet this complex dose-effect intertwining of progesterone’s effects on the endometrium should not lead to neglect the importance of the dose used. Indeed, knowing that epigenetic hazards loom large in ART should raise the concerns about any unnecessary hormonal exposure. The development of a progesterone preparation that offers physiological replacement – 25mg/day – is a first responsive step taken in this direction.
References
- de Ziegler D. Hormonal control of endometrial receptivity. Hum Reprod 1995;10:4-7.
- Bulletti C, de Ziegler D, Flamigni C, et al. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod 1997;12:1073-9.
- de Ziegler D, Bulletti C, de Monstier B, Jaaskelainen AS. The first uterine pass effect. Annals of the New York Academy of Sciences 1997;828:291-9.
