Mechanisms of Lactation-induced Infertility in Female Mice.

Lactation in mammals is associated with a period of infertility, which serves to direct maternal metabolic resources toward caring for the newborn offspring rather than supporting another pregnancy. This lactational infertility is characterized by reduced pulsatile luteinizing hormone (LH) secretion and lack of ovulation. The mechanisms mediating suppression of LH secretion during lactation are unclear. There are potential roles for both hormonal cues such as prolactin and progesterone, and pup-derived cues such as suckling, on the inhibition of reproduction. To enable future studies using transgenic animals to investigate these mechanisms, in the present study our aim was to characterize lactational infertility in mice, and to investigate the effect of removing pup-derived cues on LH secretion, time to ovulation, and kisspeptin immunoreactivity. We first confirmed that C57BL/6J mice experience prolonged anestrus during lactation, which is dependent on establishment of lactation, as removal of pups the day of parturition led to immediate resumption of pulsatile LH secretion and normal estrous cycles. Once lactation is established, however, the lactational anestrus persisted for several days even after premature removal of pups. Pharmacological suppression of prolactin following premature weaning significantly reduced this period of lactational infertility. Progesterone does not appear to play a significant role in the suppression of fertility during lactation in mice, as levels measured during lactation were not different from nonpregnant mice. These data suggest that prolactin plays a key role in mediating anestrus during early lactation in mice, even in the absence of the suckling stimulus.

Reformulation of PULSAR for Analysis of Pulsatile LH Secretion and a Revised Model of Estrogen-Negative Feedback in Mice.

The recent use of the tail-tip bleeding approach in mice has enabled researchers to generate detailed pulse and surge profiles of luteinizing hormone (LH) secretion in mice. However, the analysis of pulsatile LH secretion is piecemeal across the field with each laboratory using their own methodology. We have reformulated the once-popular PULSAR algorithm of Merriam and Wachter to operate on contemporary computer systems and provide downloadable and online pulse analysis platforms. As it is now possible to record the activity of the gonadotropin-releasing hormone pulse generator in freely behaving mice, we have been able to unambiguously define LH pulses in intact and gonadectomized male and female mice. These data sets were used to determine the appropriate PULSAR parameter sets for analyzing pulsatile LH secretion in the mouse. This was then used to establish an accurate model of estrogen negative feedback in the mouse. Intact and ovariectomized mice given Silastic capsules containing 1, 2, and 4 µg 17-ß-estradiol/20 g body weight were tail-tip bled at 6-min intervals, and the resultant LH profiles were analyzed with PULSAR. Only the 4 µg 17-ß-estradiol capsule treatment was found to return LH pulse amplitude and frequency to that of intact diestrous mice. Ultrasensitive mass spectrometry analysis showed that the 4 µg 17-ß-estradiol capsule generated circulating estradiol levels equivalent to that of diestrous mice. It is hoped that the reformulation of PULSAR and generation of a realistic model of estrogen-negative feedback will provide a platform for the more uniform assessment of pulsatile hormone secretion in mice.

The role of prolactin in co-ordinating fertility and metabolic adaptations during reproduction.

Mammalian pregnancy and lactation is accompanied by a period of infertility that takes place in the midst of a sustained increase in food intake. Indeed, successful reproduction in females is dependent on co-ordination of the distinct systems that regulate reproduction and metabolism. Rather than arising from different mechanisms during pregnancy and lactation, we propose that elevations in lactogenic hormones (predominant among these being prolactin and the placental lactogens), are ideally placed to influence both of these systems at the appropriate time. We review the literature examining the impacts of lactogens on fertility and energy homeostasis in the virgin state, during pregnancy and lactation and potential long-term impacts of reproductive experience. Taken together, the literature indicates that duration and pattern of lactogen exposure is a vital factor in the ability of these hormones to alter reproduction and food intake. Transient increases in prolactin, as typically seen in healthy virgin females and males, are unable to exert lasting impacts. Importantly, both suppression of fertility and increased food intake are only observed following exposure to chronically-elevated levels of lactogens. Physiologically, the only time this pattern of lactogenic secretion is maintained in the healthy female is during pregnancy and lactation, when co-ordination between these regulatory systems emerges. This article is part of the special issue on 'Neuropeptides'.