The effect of estradiol, progesterone, and melatonin on estrous cycling and ovarian aromatase expression in intact female mice

Objective: Melatonin and progesterone levels decline during the perimenopause. Both hormones inhibit estrogen action and endometrial cancer, but little is known about how they act in combination. Therefore, the interplay of progesterone (P-4)and melatonin was investigated in intact female mice. Study design: Three P-4 doses, low (25 mg), mid (50 mg), and high (100 mg), combined with 0.5 mg 17 beta-estradiol (E), were administered in the diet (per 1800 kcal) for 30 days. Hormone therapy (HT) with the low P-4 dose (estradiol/low progesterone replacement therapy (EPLRT)) was used to create an excess estrogen environment to mimic perimenopause. Half the mice were treated with melatonin (M) 15 mg/L in the drinking water at night. Results: The unbalanced EPLRT treatment increased estrogen-regulated responses. Specifically, mice treated with EPLRT had significantly higher levels of ovarian aromatase mRNA versus control, which was prevented in the presence of higher doses of P-4 and/or the addition of melatonin. The number of days in estrus also increased in EPLRT-treated versus control mice with no change in the length or number of complete estrous cycles. Melatonin, combined with all doses of P-4, increased the number of days spent in estrus, but not the length or number of estrous cycles compared to melatonin alone; however, two-way ANOVA revealed a significant interaction between melatonin and P-4 dose for days in estrus and for number of cycles. Although none of the E-2 and P-4 combinations significantly affected uterine weight compared to control, melatonin addition to the low or mid P-4 HT resulted in slightly higher uterine weights compared to melatonin-treated mice. Melatonin significantly increased uterine estrogen receptor alpha (ER alpha) and progesterone receptor A levels compared to control animals. HT, added in combination with melatonin, reduced ERa levels back to control levels, but PR levels remained elevated albeit intermediary to those achieved with melatonin alone. Conclusion: The findings that melatonin supplementation inhibits ovarian aromatase expression and increases uterine receptors in mice given an HT that mimics perimenopause may have important clinical applications for the improvement of menopause-related conditions, like menorrhagia, associated with high levels of E-2 and low levels of P-4. (C) 2013 Elsevier Ireland Ltd. All rights reserved.