Optimizing the Delivery of 17β-estradiol: Maximizing Beneficial Cognitive Effects While Minimizing Undesired Peripheral Stimulation in a Rat Model of Surgical Menopause

Estrogen-containing hormone therapy (HT) is approved for treatment of symptoms associated with menopause by the Food and Drug Administration. A common estrogen used in HT is 17β-estradiol (E2). Rodent models of menopause, and some clinical work as well, suggest a cognitively-beneficial role of E2. However, as of the 2017 statement released by the North American Menopause Society, HT is not currently advised for use as cognitive therapy in healthy, menopausal women, given that the data so far from existing clinical studies are not yet definitive. Indeed, the delivery of E2 treatment can be optimized to yield more consistent results on cognitive function, particularly considering that exogenously administered E2 gets rapidly metabolized and cleared from the body. Further, E2-containing HT must include a progestogen if prescribed to women with a uterus to oppose its undesired uterine stimulating effects, such as increased endometrial hyperplasia and cancer risks. Studies have shown that the addition of a progestogen to E2 treatment can attenuate the effects of E2 on cognition and brain variables associated with cognitive function. Thus, a brain-specific delivery platform of E2 treatment that would minimize the hormone’s effects in the periphery while maintaining the beneficial cognitive effects is desirable. To achieve this goal, my dissertation work bridged two distinct scientific fields – behavioral neuroendocrinology and polymeric drug delivery – with the overarching aim of targeting the delivery of E2 to the brain to achieve maximal cognitively-beneficial effects with minimal undesired uterine stimulation. This aim was addressed via three distinct delivery strategies: 1) combining E2 with a cognitively-beneficial progestogen, 2) encapsulating E2 in polymeric nanoparticles, and 3) solubilizing E2 using cyclodextrins for intranasal administration. Findings revealed that although all E2-containing treatments increased uterine horn weights, a marker of uterine stimulation, in middle-aged ovariectomized rats, some E2 treatment formulations yielded memory improvements, others were neutral in their effects on memory, and some impaired memory. Together, data from this dissertation set the stage for targeted E2 delivery research to optimize the cognitive therapeutic effects of E2 in the context of menopause while minimizing peripheral burden, leading to translationally relevant clinical implications for women’s health.