“New” estrogen and new route of administration for Safer Modulation of Estrogen Receptor activities at menopause – NOSE4

As a consequence of the pleiotropic effects of estrogens (E), the decline of their production by the ovaries at menopause often leads to functional disorders several climacteric symptoms (as hot flashes and night sweats, insomnia and mood instability) are due to E drop in the central nervous system (CNS) and affect the quality of life. E deprivation can also manifest through urogenital atrophy and sexual dysfunction, a shift towards central body fat distribution and the consequent metabolic alterations, acceleration of skin ageing and of osteopo¬rosis. Hormone therapy (HT) is efficient to prevent climacteric symptoms as well as osteoporosis, diabetes and coronary artery risk. However, HT also increases the risk of two harmful effects: thrombosis of veins (VT) and its embolic complications, and breast cancer. This underlines the need for new therapeutic options, that would retain the main beneficial effects of estrogens without or with less risk of breast cancer and/or VT. NOSE4 proposes two new options to improve the safety of ERa modulation in a perspective of HT: a new route of administration of estrogens: the intranasal route; and/or a new estrogen: Estetrol
There is no consensus concerning the administration route of E: oral in the USA, transdermal in France, this later route avoiding hepatic first pass and consequently the increase in coagulation factors and VT. The intranasal delivery route of E, as already shown for progesterone and testosterone (P2 and 5), could allow its preferential delivery to the CNS. It could enhance the desired actions (prevention of hot flushes, but also of gain weight and metabolic benefits), while decreasing the E exposure of liver and sex target organs and thereby its two related side effects (VT and breast cancer). This hypothesis will be tested in task 1.
Estetrol (E4), an estrogen synthesized by the liver of the fetus, was recently evaluated through a recent phase II clinical trial as a new oral contraceptive by Partner 4. The advantage of E4 over the other E used so far, is that E4 (up to 20 mg/day) has no hepatic impact, in particular on coagulation factors, and thus might not increase VT risk. At the same dose, E4 contributes to inhibit ovulation and to prevent uterine spotting in young women, and to prevent hot flushes at menopause. In a medical perspective of women health improvement, the aim of task 2 is to further elucidate the mechanisms of action of E4. Estrogen receptors alpha (ERa) is a ligand-dependent transcription factor that exhibit nuclear actions through binding to chromatin and mobilization of cofactors to influence the transcription of their target genes. A fraction of ERa bound to plasma membrane can elicit Membrane Initiated Steroid Signaling. Partner 1 previously demonstrated that E4 is a unique E as it activates nuclear ERa but inhibits membrane ERa. We hypothesize that liver gene expression is dependent on both nuclear and membrane ERa, and thus that the peculiar profile of E4 could explain its « liver friendly » action. Thanks to a unique set of transgenic mouse models, P1 3, and 4 will characterize the molecular and cellular mechanisms of action of E2 and E4 in the liver. Moreover, this approach could provide a model to understand one of the most intriguing mysteries of ERa biology, i.e. the tissue specificity of Selective ER Modulators.
This project will be conducted by a consortium of 3 academic partners that have complementary and acknowledged expertise: ER-mediated signaling in vivo (P1, INSERM/Univ. Toulouse, coordinator), ERa structure and function and epigenetic mechanisms (P3, CNRS Rennes), and synthesis and actions of steroids in the CNS (P2, INSERM, Bicêtre). P4 (Mithra Pharma, Belgium) patented oral E4 in contraception and HT and P5 (M et P® Pharma AG, Switzerland) patented improved intranasal drug delivery of neurosteroids will provide E4 and E nasal formulations to the consortium.