Tsouderos Y.
(Paris, France)

A nasal spray of 17 ß-estradiol solubilised in water (AERODIOL), leading to a specific plasma estradiol kinetic profile, gives the opportunity to analyse the effects of transient hormone exposure. It provides a pulse of plasma estradiol concentrations: the maximum (Cmax) occurs within 10-30 minutes and then a quick estradiol distribution to tissues leads to return to low postmenopausal concentrations within 8-12 hours. The cell exposure is therefore transient and ensures a pulsed estrogen therapy.

Estrogen therapy acts through the physiologic specific estrogen receptor (ER) pathway. In the cells 17 ß-estradiol is presented to it's specific receptors (ERa and ERP). It activates and causes a dimerisation of the receptors. The dimer binds to specific sites (ERE) on the genes. This initiates DNA transcription which leads to the formation of specific mRNA. At this point, the synthesis of the tissue specific proteins starts. A high plasma concentration helps estradiol diffusion and ER activation in a few minutes. The half life of the activated receptor has been estimated at about 5-7 hours. The time needed to synthesise a protein is much longer (12-48 hours). This complex system involving several sequential protein syntheses has indeed a great inertia.

The possibility of an estradiol pulse able to activate receptors and obtain a biological activity identical to that of estradiol at a constant level but with the same 24 hour estradiol total exposure was evaluated. In vitro experiments did not show any differences in kinetics of specific estrogen dependant mRNA production or cell proliferation (normal human and ER‑positive cancer breast cell lines). Through in vivo pharmacological experiments using the mammary cancer DMBA-induced experimental model the comparison of hormone replacement treatment, either by oral or IX routes in ovariectomised rats, showed that intravenous dose levels achieved equivalent estrogenicity, as assessed by the uterus weight, at corresponding oral dose levels and that both routes compensate dose‑dependently the estrogen deficit up to restoring a physiological uterus weight. Nevertheless, pulsed therapy leads to a significantly lower tumour incidence rate than the oral route. In addition, tumour development was lower with the I.V. route.

Clinical trials in symptomatic postmenopausal women validated the concept of pulsed estrogen therapy with comparisons to placebo and positive active controls (oral and transdermal estradiol). Contrasting with equivalent efficacy they gave evidence of a lower estrogen stimulation of the reproductive tissues when compared to the latter. the transient ER stimulation is illustrated by the analysis of the FSH plasma levels.

In conclusion, the new concept of pulsed estrogen therapy introduced by AERODIOL acts through the physiologic specific estrogen receptor pathways and results in similar or in different estrogen tissue stimulation depending on the tissue when compared to continous exposure. Therefore, the pulsed estrogen therapy may have specific clinical advantages in HRT for postmenopausal women.