Energy Availability
Biological processes require metabolic energy. In settings of restricted energy availability, maintenance of life- sustaining functions is prioritized. Pregnancy and lactation are metabolically expensive; and since reproduction is not critical for individual survival, it is metabolically gated. Inadequate energy availability suppresses re productive function: this forms the basis for both nutritional in fertility and functional hypothalamic amenorrhea. The neurobiological mechanisms underlying the influence of nutritional status on the reproductive system remain poorly understood. However, inadequate energy availability culminates in impaired GnRH and gonadotropin secretion. The reproductive effects of reduced energy availability appear to be mediated by circulating factors (e.g. leptin and insulin) in addition to com plex central neural pathways involving myriad neuropeptides (e.g. kisspeptin) and neurotransmitters.
Stress
A ‘stressor’ is a potential threat to homeostasis (e.g. injury, illness, reduced energy availability, situations that provoke psychological distress, etc.). Both marked acute stress and chronic stress can re duce reproductive function, and in some cases this can be viewed as an appropriate adaptive response. As examples, critical illness is typically characterized by a reversible hypogonadotropic hypogonadism; and psychological stress can play a role in functional hypothalamic amenorrhea. Stress- related impairment of reproductive function primarily relates to suppression of GnRH secretion. The reproductive effects of stress appear to be mediated by corticotropin- releasing hormone (CRH), arginine vasopressin (AVP), and cortisol, in addition to complex central neural pathways involving numerous neuropeptides (e.g. kisspeptin) and neurotransmitters.
Lactation
Lactation is often accompanied by amenorrhea and subfertility. In the setting of limited resources, lactational amenorrhea can be viewed as an important adaptation since short interbirth intervals could jeopardize infant well- being. In the setting of lactation, pulsatile GnRH release is slowed, rendering hypogonadotropic hypogonadism. Mechanisms remain unclear, but this in part reflects the very high metabolic cost of milk production and, thus, reduced energy availability for reproductive functions. Reduced GnRH secretion during lactation may partly reflect hyperprolactinemia, and neural mechanisms may also be important since the frequency and duration of suckling appears to impact contraceptive effectiveness.
Circadian changes and Sleep
Both basal gonadotropin secretion and LH surges may exhibit circadian patterns, but the degree to which this pertains is species dependent. For example, LH surges in female rodents are temporally constrained to the late afternoon hours; but in female monkeys and women, LH surges do not appear to be confined to a specific time of day. Similarly, although women exhibit diurnal changes in gonadotropin secretion, recent studies suggest that LH and FSH secretion does not change markedly when accounting for sleep status, body position, activity level, light exposure, and nutritional cues.
Sleep can have a profound influence on pulsatile LH (and by inference GnRH) secretion in humans, and such changes may con tribute to normal gonadotropin production across puberty and during the early follicular phase (EFP). Early puberty is characterized by a sleep- associated increase in LH pulse amplitude and frequency: this begins shortly after sleep onset and also occurs during daytime sleep. During puberty, LH pulse initiation appears to be encouraged by slow wave sleep but discouraged by rapid eye movement (REM) sleep. Sleep- related slowing of LH pulse frequency occurs in late pubertal girls and in women, most prominently during the EFP, but also in the late follicular phase. In women studied during the EFP, LH pulse initiation is encouraged by brief awakenings but discouraged by REM sleep. Naloxone appeared to prevent the sleep- associated decrease in LH pulse frequency in the EFP, suggesting that sleep- related slowing may be mediated by hypothalamic opioids.
