Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats

Although estradiol (E2) may have some beneficial effects as a treatment for menopause symptoms, E2 also has trophic effects that can increase vulnerability to some cancers, such as breast cancer. In the present study, a model to investigate the concomitant behavioral and proliferative effects of E2 was developed. First, the effects of different duration of chronic E2 exposure (2 vs 6 months), or no such exposure, on proliferation (tumor incidence and weight, uterine weight) in adult, ovariectomized (OVX) rats was determined. Second, the effects of different dosages of E2 (0.03 or 0.09 mg/kg) compared to vehicle only on sexual behavior, and measures of proliferation of adult OVX rats treated with a chemical carcinogen (DMBA; 1.25, 12.50, or 25.00 mg), or inert vehicle, were investigated. Vehicle or E2 was administered subcutaneously (SC) to OVX rats once per week for 14 weeks. Six months of continuous E2 exposure increased tumor incidence, tumor weight, and uterine weight, compared to 2 months of E2 or no E2 exposure. Rats administered DMBA had increased incidence, number, and size of tumors compared to vehicle treatment, and this effect appeared to be augmented by E2. Compared to vehicle, E2 increased lordosis and uterine weight. Thus, E2 may have the unfavorable effect of increasing proliferation when administered in chronic situations. Studies investigating the action of E2 for these effects are ongoing

Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats

Androgen levels decline with aging. Some androgens may exert anti-anxiety and cognitive-enhancing effects; however, determining which androgens have anxiolytic-like and/or mnemonic effects is of interest given the different mechanisms that may underlie some of their effects. For example, the 5α-reduced metabolite of testosterone (T), dihydrotesterone, can be further converted to 5α-androstane,17β-diol-3α-diol (3α-diol) and 5α-androstane,17β-diol-3β-diol (3β-diol), both of which bind with high affinity to the beta isomer of the intracellular estrogen receptor beta (ERβ). However, androsterone, another metabolite of T, does not bind well to ERβ. To investigate the effects of T metabolites, male rats were subjected to gonadectomy then implanted with silastic capsules of 3α-diol, 3β-diol, androsterone, or oil control. After recovery, the rats were tested in elevated plus maze (EPM), light/dark transition (LD), and Morris water maze (MWM). 3α-diol both decreased anxiety-like behavior in the EPM and LD, and increased cognition in MWM, while 3β-diol improved cognition in MWM, but had no effects on anxiety behavior, compared to vehicle or androsterone. These data suggest that the actions of 3α-diol and 3β-diol at ERβ may be responsible for some of testosterone’s anti-anxiety and cognitive-enhancing effects

Progesterone reduces depression-like behavior in a murine model of Alzheimer’s Disease

Although anxiety and depression are not the core symptoms of Alzheimer’s Disease (AD), there are changes observed in mood in those with AD, as well as in the aging population. Anxiety and depression may be influenced by progesterone P4 and/or its neuroactive metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP). To begin to investigate progestogens’ role in AD, a double transgenic mouse model of early-onset familial AD that co-overexpresses mutant forms of amyloid precursor protein (APPswe) and presenilin 1 Δ exon 9 mutation was utilized. As such, the effects of long-term (from 6 to 12 months of age) administration of P4 to ovariectomized (ovx) wildtype and APPswe+PSEN1Δe9 mice for changes in affective behavior was investigated. APPswe+PSEN1Δ9 mutant mice had increased anxiety-like (i.e., increased emergence latencies, decreased time spent on the open quadrants of the elevated zero maze) and increased depressive-like behavior (i.e., increased time spent immobile) than did wildtype mice. Compared to vehicle-administration, P4 administration (which produced physiological circulating P4, DHP, and 3α,5α-THP levels, particularly in the wildtype mice) decreased depressant-like behavior in the forced swim test. These effects occurred independent of changes in general motor behavior/coordination, pain threshold, and plasma corticosterone levels. Thus, the APPswe+PSEN1Δ9 mutation alters affective behavior, and P4 treatment reversed depressive-like behavior