Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle‐aged ovariectomized female rats

Abstract

While some research has indicated that ovarian hormone therapy (HT) benefits memory and decreases risk of Alzheimer's disease in menopausal women, several newer studies have shown null or detrimental effects. Despite the null and negative cognitive findings, the numerous studies showing positive effects beg the question of what factors determine whether HT acts as a neuroprotectant or a risk factor for brain functioning. Using middle-aged female rats, we directly compared six HTs. We evaluated the effects of ovariectomy, tonic low-dose, tonic high-dose and biweekly cyclic estradiol treatment, as well as whether progesterone altered the effectiveness of any one of these oestrogen regimens. Animals were tested on spatial and complex cued (intramaze patterns) reference memory using variants of the Morris maze. The tonic low-dose and cyclic estradiol treatments improved spatial performance, while the addition of progesterone reversed these beneficial cognitive effects of estradiol. Additionally, all groups learned to locate the platform on the cued task; however, an egocentric circling strategy was used with sham ovary-intact and hormone-replacement groups showing the most efficient search strategy. Although the question of memory retention 8 weeks after the first cognitive assessment was addressed, a large number of animals died between the first and second test, rendering the retest uninterpretable for many group comparisons. Specifically, both doses of tonic estradiol dramatically increased the number of deaths during the 17-week experiment, while the cyclic estradiol treatment did not. Progesterone decreased the number of deaths due to tonic estradiol treatment. Our findings suggest that the dose of estradiol replacement as well as the presence of progesterone influences the cognitive outcome of estradiol treatment. Further, there appears to be a dissociation between HT effects on cognition and mortality rates.

Progesterone and Estrogen Regulate Alzheimer-Like Neuropathology in Female 3xTg-AD Mice

“…For example, we recently reported that, although P4 treatment in female OVX rats did not affect the extent of kainateinduced neuron loss, it completely blocked E2 neuroprotection (Rosario et al, 2006a). Similarly, continuous P4 treatment has been reported to inhibit E2-mediated increases in neurotrophin expression (Bimonte-Nelson et al, 2004) and spatial memory performance (Bimonte-Nelson et al, 2006). One particularly interesting component of this relationship with hypothesized clinical relevance is the effect of continuous versus cyclic P4 treatment.…”

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

“…It has been well-established that estrogens influence memory and cognition [7,8], decrease the risk and/or delay the onset of neurological diseases (e.g., AD and PD), and attenuate the extent of cell death that results from a variety of insults involving ROS-induced oxidative stress implicated among others in stroke or neurotrauma [9,10]. Various in vitro and in vivo models show that estrogens are capable to protect neurons in a concentration range of 0.1 nM to 50 µM suggesting the involvement of different modes of action [11][12][13][14][15].…”

Evaluating the Role of Hormone Therapy in Postmenopausal Women with Alzheimer’s Disease

“…The remaining preclinical research has been done on ovariectomized females treated with 17β-estradiol with results showing the beneficial effect of estrogen on cognition (Table 1) [48][49][50]. Metaanalyses of HT effect on cognition revealed that time-limited positive estrogen treatment effect was seen in women who had recently undergone surgical menopause [51].…”

“…However, animal studies more commonly use subcutaneous pellets and silastic capsules to deliver HT (Tables 1 and 2) [49,83,78,88,90].…”