The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock-driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility.
Goldstein CA et al., 2016·Current Sleep Medicine Reports
Adequate sleep is crucial for general health and wellbeing. Although the neuronal control of the reproductive axis and sleep-generating neurons share an anatomical location, little is known regarding the impact of sleep and circadian disruption on fertility in women. Animal models have established clear circadian control of the pre-ovulatory luteinizing hormone surge. Additionally, disruption of the circadian timing system by exposure to abnormal light-dark cycles or mutations of core clock genes results in diminished reproductive capacity in animals. Abnormalities in menstruation, fertility, and early pregnancy maintenance in female shift workers provide evidence for a role of circadian rhythms in the reproductive health of women. Reproductive hormones may modify sleep, and the relationship is bidirectional such that sleep disruption may alter the profile of reproductive hormone secretion. Therefore, sleep, apart from its circadian timing, may also have relevance in attaining pregnancy. Additionally, infertility is associated with psychological distress which may result in poor quality sleep. The interaction between psychological distress and disturbed sleep in reproduction has garnered minimal attention and may be a crucial factor to consider during the evaluation and treatment of infertility. This work reviews animal models and evidence in women that suggest a role for sleep and circadian rhythms in reproductive health and reveals areas that require future investigation.
A push-pull perfusion (PPP) system was used to carry out the first examination of LHRH release from the mediobasal hypothalami (MBH) of conscious, freely moving rats during stages of the estrous (E) cycle and after ovariectomy (Ovx). Female rats received push-pull cannula (PPC) implants into the MBH and then were allowed to recover for 2–10 weeks before PPP experiments. During that time, E cycles were determined by daily inspection of vaginal smears. After exhibiting two consecutive E cycles, rats were fitted with indwelling jugular catheters between 0830–1030 h and subjected to PPP of the MBH and hourly bleeding for more than 6 h. LHRH and LH levels were determined by RIA in perfusates and plasma, respectively. PPP and bleeding sessions were performed on the afternoon of proestrus (Pro; n – 10), diestrous day I (DI; n – 5), diestrous day II (DII; n – 5), estrus (E; n – 5), or more than 28 days after Ovx (n – 5). LHRH output was detectable in at least some samples in all rats whose PPC tips resided within 0.5 mm of the rostrolateral median eminence. Basal LHRH output (<0.2 to 1.2 pg.12 min) appeared to be pulsatile in all groups. During Pro, higher LHRH levels permitted pulse frequency determinations (average Pro interpulse interval, 48.0 min). Overall LHRH output during Pro was elevated (P< 0.01) compared to that in all other groups and was distinctly biphasic; a putative priming pulse (P < 0.05) occurred 2–3 h before the occurrence of a larger main peak (1.6–7.0 pg-12 min) at approximately 1600–1730 h (lights on from 0500–1900 h). Proestrous (Pro) LH levels in rats bearing PPC implants were only 10–30% of those in intact rats regardless of PPP. Nonetheless, these rats did exhibit temporally normal Pro LH surges concident with LHRH release. In DI and DII rats, LHRH pulse amplitude increased moderately for a brief period in the late afternoon (P < 0.01 only when data was normalized to the largest peak). LHRH output in E rats was low and mostly undetectable. Pulse amplitude in ovariectomized (Ovx) rats remained constant and low throughout the afternoon, while LH levels were elevated to typical post-Ovx values. We conclude from this study that (1) a biphasic LHRH surge occurs on the afternoon of Pro which may act to prime and then stimulate pituitary gonadotrophes, (2) small but significant increases in LHRH pulse amplitude occur between 1500–1900 h in DI and DII rats, but not in Ovx or E rats, and (3) LH, but not LHRH, release is increased in Ovx rats, suggesting that the negative feedback effects of ovarian steroids operate primarily at the level of the pituitary gland.
Ovariectomized rhesus monkeys bearing hypothalamic lesions which had abolished endogenous LHRH production, as evidenced by a profound reduction in gonadotropin secretion, but in which LH and FSH secretion was reestablished by a chronic intermittent iv infusion of synthetic LHRH (1 microgram/min for 6 min every hour) were used to investigate the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion. The administration of estradiol to such animals, while continuing the LHRH replacement regimen, resulted in a decline in circulating LH and FSH levels, followed by an unambiguous discharge of these hormones. The time course of this biphasic pattern of gonadotropin secretion was remarkably similar to that observed in response to estradiol administration in otherwise intact ovariectomized animals. These results suggest that, in the rhesus monkey, estradiol can exert both its negative and positive feedback actions on gonadotropin secretion at the level of the pituitary gland.
Casto KV et al., 2022·Frontiers in neuroendocrinology
Oral contraceptives (OCs) are widely used yet understudied given their potential for public health consequences. Emerging investigations scaling from single-subject, dense-sampling neuroimaging studies to population-level metrics have linked OCs to altered brain structure and function. Modeling the hypogonadal, hypergonadal, or mixed state effects of OCs in terms of their impact on hormone action in the brain is a valuable approach to synthesizing results across neuroimaging studies and comparing OC effects to companion findings from research on menstrual cycle phase effects on brain anatomy and function. Resting-state functional connectivity studies provide a powerful tool to evaluate the role of OCs on the intrinsic network connectivity that underlies multiple behavioral domains. The preponderance (but not consensus) of the current literature indicates that (1) as the menstrual cycle proceeds from a low to high progesterone state, prefrontal connectivity increases and parietal connectivity decreases; (2) OCs tend to mimic this connectivity pattern; therefore (3) OCs may produce a hyperprogestogenic state in the brain, in spite of overall reductions in endogenous steroid hormone levels. Alternative models are also considered.