“All in the Mind”? Brain-Targeting Chemical Delivery System of 17β-Estradiol (Estredox) Produces Significant Uterotrophic Side Effect

Abstract

Here we revisit the peculiarly named redox chemical delivery system concept. This unique prodrug approach has long been claimed to be capable of targeting 17β-estradiol (E2), which has numerous beneficial central effects, into the brain without detrimental peripheral hormonal exposure. Using a well-established protocol to monitor E2’s antidepressant–like effect, we show that the administration of this chemical delivery system incorporated into hydroxypropyl-β-cyclodextrin (i.e., Estredox), indeed, triggers a transient antidepressant-like behavior in ovariectomized mice. At the same time, even an acute dose of the carefully purified chemical delivery system produces significant circulating E2 levels and uterotrophic side effects for several days after drug administration. For the first time, we also unequivocally show by liquid chromatography coupled with tandem mass spectrometry that the uterus of the Estredox-treated animals contains a large quantity of E2 compared to that of the control group. These thus far unexposed yet consequential peripheral side effects brought about by Estredox call for a thorough and unbiased reassessment of the extent of brain-targeting of the hormone via the chemical delivery system approach.

The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders

“…S3A,B), DHED treatment did not result in wet uterus weight gain (Fig. 6A), which is a uterotrophic effect of systemically administered estrogens (15, 29). This was independent of the route of administration (i.v., s.c. or p.o.)…”

17β-Estradiol Eye Drops Protect the Retinal Ganglion Cell Layer and Preserve Visual Function in an in Vivo Model of Glaucoma

“…64 Indeed, we found that the wet uterus weight in the E2 group was approximately five-times higher than in the control group, indicating that a significant uterine stimulation was brought about by E2 eye drop treatments. Previously we have shown 65 that the uterotrophic effect triggered by high levels of circulating E2 also results in significantly increased E2 content in the uterus that may be directly responsible for the increased risk for developing endometrial cancer.…”

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

“…The novel chemical entities ( 2 and 3 ) were cleaved from the resin with trifluoroacetic acid/water 98:2 ( v / v ) and purified by semi-preparative reversed-phase high-performance liquid chromatography (RP-HPLC). For the preparation of the bioprecursor prodrugs 4 and 5 (Figure 2), the TRH analogs ( 2 and 3 ) were reduced to the corresponding neutral dihydropyridines ( 4 and 5 ) with a well-established and straightforward method using sodium dithionite [2,3,28,37,39]. The identity and purity of the test agents were confirmed by liquid chromatography-mass spectrometry (LC-MS) and analytical RP-HPLC.…”

“…Behavioral studies for antidepressant-like activity were conducted with a validated model, as reported before [16,37,39,40]. Test compounds were administered i.v.…”