Cognitive effects of long-term dydrogesterone treatment used alone or with estrogen on rat menopausal models of different ages

Menopause can cause cognitive decline. Hormone Replacement Therapy (HRT) is the most effective treatment for the climacteric symptoms. However, its cognitive effect has not been well clarified, especially for the progestin component. The study investigated the effects of dydrogesterone (DG) on spatial learning and memory of the ovariectomized (OVX) rat models and the impact of aging on its cognitive effects. Eighty female Sprague-Dawley rats were included in the experiment. They belonged to two cohorts, the adult (7 months) and the aged (18 months). Each cohort was divided into five groups: Sham, OVX, OVX + E2 (OVX + 17β-estrogen), OVX + E2/DG and OVX + DG. The replacement therapy lasted for 20 weeks. Two classical behavioral tests were performed: open field test (OFT) and the Morris water maze (MWM). The breast morphology and uterine weight were obtained to assess the safety and complication of dydrogesterone. In MWM, the OVX group displayed prolonged latency and less target quadrant time than the other groups. Across 5 days' testing, all the adult groups receiving hormone therapy, except the OVX + DG group, performed better than the OVX group (P < 0.001); but there was no significant difference among the aged groups. The uterus weight/body weight ratio of OVX + E2/DG group was lower than the sham and OVX + E2 group. The mammary glands of OVX + E2/DG group displayed normal structure or mild hyperplasia. The results suggested that DG-alone treatment had no significant benefit for the OVX rats of both adult and aged groups on the behavioral tests. DG combined with E2 could ameliorate cognition in adult rats with uterus protection and without breast harm. The cognitive-improve effects were more remarkable for the adult rats than the aged ones. The findings support the potential clinical application of dydrogesterone combined with estrogen in preventing cognitive decline, especially for the early iatrogenic menopausal women.