Physiological Pineal Effects on Female Reproductive Function of Laboratory Rats: Prenatal Development of Pups, Litter Size and Estrous Cycle in Middle Age

Abstract

The present study investigates whether and how the pineal or its hormone melatonin influences female reproductive functions, namely the litter size, prenatal development of offsprings, and estrous cyclicity, especially its age-related cessation in a non-seasonal breeder, the laboratory rat. Wistar rats were maintained under a 24 h light-dark (12Lratio12D) cycle. Female rats were divided into 3 groups: non-operated (NO), sham-operated (SX), and pinealectomized (PX). Surgeries were performed in 35-40 day-old females. Starting at an age between 70 days and 7 months, female rats of all 3 groups were repeatedly mated with intact males. PX mothers more frequently delivered pups with malformations (e.g., taillessness, hydronephrosis, 7 out of 1263 pups) than control rats (0/1323; p<0.007). In the first delivery at 3 months of age, but not at later ages, PX mothers delivered more pups of lower body weight than control animals (p<0.001). Examination of vaginal smears showed that almost all female rats of the NO, SX, and PX groups had 4-day estrous cyclicity when they were young-between 60 days and 5 months of age. At an age of 17 to 18 months, most female rats of the NO and SX groups showed irregular, continuously diestrous or pseudopregnancy-like patterns, and 4-day estrous cyclicity was found in only 10% of the NO or SX animals. In contrast, about 50% of the PX rats showed 4-day estrous cyclicity at this older age (p< 0.001). Melatonin, when added to drinking water (0.4 mg/L) for 16 days during the dark phase increased the frequency of diestrous phase, except in continuously diestrous rats and very few others. This melatonin effect was strong in PX rats but relatively weak in SX rats. In conclusion, the pineal hormone appears to influence various reproductive functions and developmental processes, especially pregnancy and the timing of reproductive aging in rats. The effects of pinealectomy are more prominent at an age of 60 to 80 days (i.e., shortly after puberty) and at the beginning of the cessation of cycles in middle-aged females.

Effects of melatonin on the endometrial morphology and embryo implantation in rats

“…Pineal gland ablation may also induce an increase in the production of E and interfere with the pituitary release of LH and FSH (23), resulting in an anovulatory state and noncycling rats (24,25). Accordingly, our data mainly show a prolonged estrous phase, an event that may be related to the increase in the levels of E and a decrease of those of P.…”

Timed Maternal Melatonin Treatment Reverses Circadian Disruption of the Fetal Adrenal Clock Imposed by Exposure to Constant Light

“…The detection of growth retardation inside such a short time window is not surprising, considering that in the rat fetal growth is exponential and maximal by the end of gestation [36]. Furthermore, comparable intrauterine growth restriction, together with placental edema, fibrin accumulation and leukocyte infiltration have been reported in rat pregnancy under constant light [37], whilst maternal pinealectomy induced an increase in pup malformations with low weight at birth [38]. Indeed, our biometric results in the rat are consistent with epidemiological studies of human pregnancy subjected to chronodisruption pointing to an increased risk of miscarriage, preterm delivery and particularly low birth weight [2]–[5].…”

Long-term melatonin treatment reduces ovarian mass and enhances tissue antioxidant defenses during ovulation in the rat

“…It is known that melatonin can increase the diestrous frequencies or estrous phases in rodents (31) by modulating GnRH hormones, but the exact mechanisms involved are poorly understood. Thus, it seems true that nutritional improvements were not effectively responsible for maintaining regular cycles.…”