Impact of continuous versus discontinuous progesterone on estradiol regulation of neuron viability and sprouting after entorhinal cortex lesion in female rats

Because the estrogen-based hormone therapy (HT) in postmenopausal women typically contains a progestogen component, understanding the interactions between estrogens and progestogens is critical for optimizing the potential neural benefits of HT. An important issue in this regard is the use of continuous vs discontinuous hormone treatments. Although sex steroid hormone levels naturally exhibit cyclic fluctuation, many HT formulations include continuous delivery of hormones. Recent findings from our laboratory and others have shown that coadministration of progesterone (P₄) can either attenuate or augment beneficial actions of 17 β-estradiol (E₂) in experimental models depending in part upon the delivery schedule of P₄. In this study, we demonstrate that the P₄ delivery schedule in combined E₂ and P₄ treatments alters degenerative and regenerative outcomes of unilateral entorhinal cortex lesion. We assessed how lesion-induced degeneration of layer II neurons in entorhinal cortex layer and deafferentation in dentate gyrus are affected by ovariectomyandtreatments with E₂ alone or in combination with either continuous or discontinuous P₄. Our results demonstrate the combined efficacy of E₂ and P₄ is dependent on the administration regimen. Importantly, the discontinuous-combined E₂+P₄ regimen had the greatest neuroprotective efficacy for both end points. These data extend a growing literature that indicates qualitative differences in the neuroprotective effects of E₂ as a function of cotreatment with continuous versus discontinuous P₄, the understanding of which has important implications for HT in postmenopausal women.