Comparison of Estetrol Exposure between Women and Mice to Model Preclinical Experiments and Anticipate Human Treatment

Abstract

Estetrol (E4) is a natural estrogen with promising therapeutic applications in humans. The European Medicines Agency and the Food and Drug Administration have approved the use of 15 mg E4/3 mg drospirenone for contraceptive indication. Phase III clinical trials with 15–20 mg E4 for the relief of climacteric complaints are currently running. Relevant data from preclinical animal models are needed to characterize the molecular mechanisms and the pharmacological effects of E4 and possibly to reveal new therapeutic applications and to anticipate potential adverse effects. Therefore, it is important to design experimental procedures in rodents that closely mimic or anticipate human E4 exposure. In this study, we compared the effects of E4 exposure after acute or chronic administration in women and mice. Women who received chronic E4 treatment per os at a dose of 15 mg once daily reached a steady state within 6 to 8 days, with a mean plasma concentration of 3.20 ng/mL. Importantly, with subcutaneous, intraperitoneal or oral administration of E4 in mice, a stable concentration over time that would mimic human pharmacokinetics could not be achieved. The use of osmotic minipumps continuously releasing E4 for several weeks provided an exposure profile mimicking chronic oral administration in women. Measurements of the circulating concentration of E4 in mice revealed that the mouse equivalent dose necessary to mimic human treatment does not fit with the allometric prediction. In conclusion, this study highlights the importance of precise definition of the most appropriate dose and route of administration to utilize when developing predictive preclinical animal models to mimic or anticipate specific human treatment.

Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model

“…At the 15th postoperative day, the time necessary for the establishment of endometrioticlike lesions [24,25], animals received subcutaneous mini osmotic pumps (Alzet, model 2004; 0.25 µL/h), releasing E 4 at dose 3 mg/kg/day (Pantarhei Bioscience, Zeist, The Netherlands) solved in the vehicle (polyethylene glycol + dimethyl sulfoxide) for the following 4 weeks (Scheme 1). The half-life of E 4 in rodents is 2-3 h. It has been reported the use of osmotic mini pumps in mice provides a constant level of circulating E 4 for several weeks compared with subcutaneous, intraperitoneal, or oral administration of E 4 [26]. The treatment duration and dose were based on previous studies that analyzed the effect of E 4 alone [27,28] or in combination with E 2 [29,30].…”

The intersection between menopause and depression: overview of research using animal models

“…Thus, the use of animal models can help to elucidate the mechanisms involved in diseases and alterations during human menopause, contributing to solving health problems at this physiological stage in women. Additionally, these models allow us to understand the physiological, endocrine, and neural mechanisms associated with the menopausal transition, and to evaluate potential therapeutic strategies to restore such alterations, which could contribute to improving the quality of life of this group of women ( 15 – 17 ).…”

Role of membrane estrogen receptor alpha (ERα) in the rapid regulation of male sexual behavior

“…It displays a moderate affinity for ERα and ERβ with a 4 to 5 fold preference for ERα 36 . E4 is quickly bioavailable and eliminated from the bloodstream following acute administration with a half‐life of 2 h in rodents 37,38 . Although its functions in humans remain unknown, it acts as a weak estrogen in various tissues in rodents, including the brain, 39 bone, 40 vagina 41 and uterus 42,43 .…”

“…36 E4 is quickly bioavailable and eliminated from the bloodstream following acute administration with a half-life of 2 h in rodents. 37,38 Although its functions in humans remain unknown, it acts as a weak estrogen in various tissues in rodents, including the brain, 39 bone, 40 vagina 41 and uterus. 42,43 By contrast, it does not activate but antagonizes the membrane pool of ERα in some tissues 42 thus providing a pharmacological means to tease appart the two modes of action of estrogens.…”