Melatonin for premenstrual syndrome: A potential remedy but not ready.

Premenstrual syndrome (PMS) is a kind of neuroendocrine disorder that threatens women’s physical and mental health. It is estimated that more than half of women complain of somatic or emotional discomfort during the luteal phase of the menstrual cycle. In general, these symptoms are mild, and some physical disturbances, such as abdominal swelling and breast tenderness, and mood changes, such as irritability and anxiety, are commonly reported ( 1 – 3 ). However, approximately 5.3% of women experience distress that is too severe, such as insomnia, depression and cognitive impairment, to accomplish daily activities ( Table 1 ). This severe form of PMS is defined as premenstrual dysphoric disorder (PMDD) ( 5 ). Although the etiology of PMS is not fully illustrated, ovarian hormone fluctuations are clearly associated with PMS, as the symptoms are only observed in the luteal phase and reduced after menstruation. Consequently, in recent years, dysfunctional reproductive hormone levels and their effects on the brain neurotransmitter system have been regarded as key factors in PMS pathogenesis ( 5 , 14 , 15 ). In line with this notion, ovarian cyclicity disruption and brain neurotransmitter regulation have been developed as treatment methods for PMS. Serotonin reuptake inhibitors (SSRIs) are recommended as the first-line therapy for PMDD management ( 5 ). However, first-line medications fail to completely relieve symptoms in almost 75% of PMDD patients. As a result, other therapeutic drugs with proof of molecular mechanisms and clinical trials are needed ( 2 ). To our knowledge, the therapeutic effect of two or more medicine combinations is always better than that of one medicine alone. For example, oral contraceptives, such as ethinylestradiol drospirenone, can further improve the management of symptoms other than depressive symptoms by suppressing the hypothalamic-pituitary-ovarian axis in PMS and PMDD ( 16 ). Ulipristal acetate, a selective progesterone receptor modulator, may be the key to alleviating psychological symptoms such as depression ( 17 ). Clinical manifestations of premenstrual syndrome. ↓ means reduced. Melatonin is produced from the pineal gland and serves as an internal synchronizer under the tight control of the central circadian timing system (internal clock) located in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus ( 18 ). Three decades ago, Parry and his colleagues found a phase-advanced offset of melatonin secretion in PMS ( 19 ). A subsequent study demonstrates an altered phase-shift response of melatonin to light in PMDD patients, whereas the suppressive effects of light on melatonin between PMDD and healthy women are similar, indicating the contribution of circadian clock dysfunction in PMDD ( 20 , 21 ). Melatonin also reciprocally modulates the circadian clock via the melatonin receptors MT1 and MT2 ( 22 , 23 ). In addition, several studies also report that nocturnal melatonin changes are accompanied by sleep, emotion and ovarian hormone alterations and that an exogenous supplement of melatonin can partially correct them ( 24 , 25 ). More importantly, progressive advances have shown melatonin’s improvement of reproductive functions and neuroprotection ( 26 , 27 ). These studies suggest that blunted circadian melatonin might contribute to PMS and imply a potential therapeutic effect. In this article, we review the latest literature on PMS and melatonin and their potential relationships from both behavioral and molecular perspectives. Regarding behavioral aspects, accumulating studies have demonstrated that melatonin has an antiPMS function in cell models, animal models and humans ( Figure 1 ). Regarding molecular mechanisms, we focused on circadian genes ( 28 ), proinflammatory cytokines (IL-6, IL-1β, TNF-α, IFN-γ, and mTOR) ( 28 – 30 ), enzyme activity ( 31 ), ovarian hormone estrogen and progesterone ( 32 , 33 ), gamma-amino butyric acid (GABA) and brain-derived neurotrophic factor (BDNF) alterations in PMS ( 34 , 35 ) ( Figure 2 , Tables 2 , 3 ). This work attempts to unravel the enigma of how melatonin modulates PMS symptoms through these molecule-related pathways, which may provide a theoretical foundation for melatonin-targeted treatment in PMS and PMDD. Mechanisms of melatonin restoration in PMS/PMDD-related symptoms, given cells, animals, and humans. Melatonin is involved in many aspects of PMS/PMDD. In cells, melatonin can upregulate GABA levels and its current among neurons, promote memory formation, and increase neuron excitability. To adjust the imbalance of the ovary’s hormones, melatonin can increase the levels of StAR and progesterone, and decrease the level of estrogen. In animals, dysfunction of sleep-wake rhythm, GABA current, memory function, cognition, and reproduction hormone balance have been modulated by melatonin intake. Meanwhile, melatonin’s improvement of sleep, memory, and cognition is also discovered in the zebrafish model. In humans, the effect of melatonin has long been applied in improving sleep quality. In PMS/PMDD-related symptoms, melatonin can restore stage-2 sleep and reproductive hormone balance and reduce slow-wake sleep, cognitive damage, and depressive/anxiety mood derived from PMS/PMDD. Potential molecular actions of melatonin in modulating premenstrual symptoms. By affecting the expression of relevant molecules, and melatonin can achieve its protective effects in PMS. Per1/2, Cry1/2, and Nr1d1 are circadian genes, melatonin can upregulate their expression to improve circadian rhythm and sleep quality. IL-6, IL-1β, TNF-α, IFN-γ, and mTOR signaling pathways and increased corticosterone levels participate in the inflammation and oxidative stress of PMS, and melatonin can downregulate these processes to play a role in neuroprotection and antidepression. Regarding enzyme activity, melatonin can upregulate the activity of acetylcholine esterase, monoamine oxidase, and Na+/K+-ATPase to promote neural activity, energy metabolism, cognition, and so on. An imbalance of reproductive hormone is seen as a pathogenesis of PMS, melatonin can upregulate the levels of StAR, CYP11A1, and progesterone receptor A and downregulate the levels of luteinizing hormone and ovarian aromatase to reverse the imbalance of the estrogen/progesterone ratio. Moreover, melatonin can promote neural transduction by increasing GABA levels and GABA-induced current, which is associated with better circadian rhythm, neuroprotection, and antianxiety effects. In addition, melatonin can act as a neurotrophic promoter by upregulating the BDNF-TrkB signaling pathway and the expression of CREB/BDNF and GDNF. Selected therapeutic effects of melatonin in PMS/PMDD-associated symptoms. Expression changes and melatonin effects in PMS/PMDD-related symptoms and animal models. The symbol ↓ means decreased while the symbol ↑ means increased.

The core symptoms of PMS, such as sleep disturbance, depression, and cognition disorders, suggest the participation of neurobiological processes in PMS and PMDD. To date, the role of the serotonin system in PMS has been elucidated. Serotonin and its receptors are not only involved in the behavioral regulation of PMS but also mediate the actions of estrogen and progesterone on the brain ( 150 ). Serotonin-targeted therapy, such as SSRIs, is recommended as the first-line treatment in PMDD. However, other critical brain neurotransmitters and neuromodulators, such as GABA and BDNF, have not been fully investigated in PMS. Hence, we review recent progress on the relationships between GABA/BDNF and PMS/PMDD. Moreover, the latest studies on melatonin-GABA/BDNF interactions are also recapitulated, anticipating the potential neurological pathways of melatonin-PMS interactions. GABA is the main inhibitory neurotransmitter in the central nervous system, participating in sleep, mood and synaptic plasticity regulation. In PMDD patients with mood disorders, GABA concentrations are dramatically reduced in the brain cingulate cortex, medial prefrontal cortex and left basal ganglia compared to healthy women ( 11 ). The GABA type A receptors (GABAARs) also suggest their involvement in the pathogenesis of PMS/PMDD. During the high progesterone phase, δ subunit–containing GABAAR (δGABAAR) expression is significantly increased, resulting in decreased neural excitability and anxiety ( 151 ). Diminished cyclic changes in δGABAARs conversely attenuate excitability ( 152 ). Further studies have demonstrated that ovarian cycle-linked δGABAAR changes in the hippocampus affect γ oscillations, which may contribute to cognitive and memory deficiencies in PMS/PMDD ( 10 ). Potential mechanisms of GABAAR changes may be the response to neuroactive steroid fluctuations such as estradiol and progesterone. In an animal model of PMDD, rapid withdrawal of progesterone increases anxiety-like behaviors and elevates the expression of GABAARs α4 submit ( 153 ). Specifically, allopregnanolone, a modulator of GABAARs, is able to enhance GABA effects and is associated with the negative emotions of PMDD. Antagonizing its effects on GABAARs also yielded promising outcomes in attenuating PMS-related symptoms ( 154 ). Moreover, in a PMS rat model, a Japanese herbal medicine, Inochinohaha White, attenuates anxious behavior by upregulating GABAAR-mediated signaling via an increase in the β2 subunit ( 155 ). By targeting the GABA system, sepranolone has indicated its potential in PMDD treatment with good tolerance and safety to a certain extent ( 156 ). Taken together, these studies demonstrate the connection between the GABA system and PMS symptoms. GABA-targeted therapy may serve as a beneficial option in PMS treatment. Although the relationship between melatonin and GABA in PMS is not fully understood, melatonin and GABA system interactions are well established. Melatonin can directly affect the GABA system ( Tables 2 , 3 ). Prado and his colleagues found that melatonin disrupts the circadian changes in GABA with increased GABA levels during the daytime ( 50 ). In the hippocampus, melatonin shows distinct effects on the GABA system according to the experimental conditions and melatonin concentrations. In vitro , melatonin elevates the amplitude and frequency of GABAergic inhibitory currents and transmission ( 34 ). In contrast, melatonin can enhance neuron excitability and depress GABAAR expression via the activation of MT1 receptors in vivo ( 51 ). In addition, the GABA system may also mediate melatonin’s regulation of sleep, emotion, circadian clock and GnRH neurons. In rats, activation of GABAARs decreases the sleep-promoting effects of melatonin ( 52 ). In addition, scientists have found that melatonin prevents anxiety-like behaviors by blocking the α2 subunit of GABAARs ( 53 ). Moreover, melatonin and circadian system interactions also involve GABA system regulation. On the one hand, by preventing GABA transmission in the SCN, daytime melatonin secretion is significantly increased, indicating that GABA controls SCN inhibition of melatonin ( 67 ). On the other hand, melatonin results in SCN neuron excitability by GABA transmission regulation ( 54 ). Similar interactions between GABA and melatonin are also found within GnRH neurons. Ishii etal. ( 55 ) found that GnRH neurons can downregulate the expression of MT1 and modify melatonin-induced GABA/GABAAR current decreases. Complementary research was conducted, and melatonin was found to modulate GABAAR-mediated GnRH excitability through melatonin receptors ( 56 ). In combination with the current literature on the interaction between melatonin and the GABA system, the hypothesis that melatonin may regulate PMS symptoms via the modulation of the GABAergic neurotransmitter system is reasonable, and further studies should be conducted. BDNF, a neural growth factor in the brain, is involved in mood regulation, synaptic plasticity, neuronal growth and survival and other crucial physiological processes. To date, researchers have focused on BDNF changes in PMS patients, and the results indicate the role of BDNF in PMS symptoms and etiopathogenesis. In PMDD patients, higher serum BDNF levels are found in the luteal phase than in normal controls ( 12 ). Similar results were found by Oral etal. ( 13 ), who showed significantly elevated BDNF levels from the follicular to luteal phase. These differences between PMDD and healthy people may be attributed to compensatory BDNF increases to alleviate depression symptoms during the luteal phase. However, the results on BDNF changes in PMS are not consistent. A contradictory study found that BDNF is significantly decreased in the luteal phase compared to the control, and decreased BDNF levels are often accompanied by negative emotions such as anxiety and depression ( 68 ). In addition, BDNF levels are reduced from the follicular to luteal phase. In a PMS rat model, BDNF expression is significantly decreased with the activation of opioid receptors ( 157 ). These inconsistent results may indicate distinct neuromodulator response alternations between PMS and PMDD. The BDNF Val66Met polymorphism, which can reduce BDNF bioactivity, has also been associated with neuropsychic disorders. In mice injected with human BDNF Val66Met, increased anxiety-like behaviors during the estrous phase are observed ( 158 ). In PMDD patients, suppressed fronto-cingulate cortex activity is observed and associated with the BDNF Val66Met allele ( 159 ). Similar to the GABA system, BDNF intersects with ovarian hormone and PMS neurological hallmarks. Steroid regulation of emotion is also dependent on BDNF and its single-nucleotide polymorphism ( 160 ). With a gradual understanding of the relationship between melatonin and BDNF, despite a paucity of direct evidence, the melatonin-BDNF pathway has been indicated as the potential mechanism of PMS pathogenesis ( Table 3 ). According to the current literature, at least two aspects can be summarized to comprehend this possible mechanism. First, melatonin regulates depression, cognition and memory via BDNF-related molecular processes. In a mouse model of depression, melatonin displays antidepression effects with the elevation of BDNF levels in the hippocampus ( 35 ). Similar effects of melatonin are also observed when combined with fluoxetine treatment, which involves the normalization of hippocampal BDNF-tropomyosin receptor kinase B (TrkB) signaling ( 42 ). Apart from emotional changes, cognitive impairment is also common in PMS patients. To date, researchers have found that cognitive damage is attenuated after melatonin treatment by increasing BDNF and TrkB expression in the dentate gyrus, cerebral cortex and hippocampus ( 69 , 161 ). Melatonin can also regulate long-term memory processes. Sung and colleagues revealed that melatonin can enhance memory formation by increasing both the cyclic adenosine monophosphate response element-binding protein (CREB) and BDNF levels ( 44 ), indicating alterations in the CREB-BDNF signaling pathway. Given the characterized depression, cognition and memory lesions in PMDD patients, melatonin regulates PMS via BDNF-related pathways. In addition, pharmacological studies on melatonin receptor agonists have also provided new insight into melatonin-BDNF interactions in PMS. For example, agomelatine, an agonist of MT1 and MT2 receptors, can increase hippocampal BDNF expression and BDNF-positive neurons in rats ( 43 ). Agomelatine also corrects disturbed sleep-wake rhythms and sleep architecture through the elevation of MT1 receptors and BDNF levels ( 40 ). As a novel antidepressant, agomelatine reduces anxiety-like behaviors and upregulates BDNF levels in the dentate gyrus ( 70 ). Per1 and Per2 expression in the SCN is concomitantly decreased. In a chronic stress model, mice showed restored memory function and elevated CREB/BDNF expression after agomelatine application ( 45 ). Another melatonin receptor agonist, ramelteon, improves depression and anxiety symptoms by increasing BDNF levels and targeting clock genes (e.g., Per1 and Per2) ( 28 ). Taken together, these studies demonstrate BDNF pathway alterations in melatonin’s action on sleep, emotion, cognition and memory, indicating new perspectives on understanding the potential involvement of melatonin in PMS and PMDD.

Undoubtedly, cyclical changes in neuroendocrine factors are tightly associated with PMS and PMDD. Ovarian hormone fluctuations during the luteal phase, such as decreased estrogen and elevated progesterone, can induce brain GABA and BDNF changes, which may ultimately contribute to PMS behavioral complaints such as sleep disturbance and mood and cognitive disorders. In this review, we summarize the potential pathogenesis of PMS and the regulation of melatonin on these processes through melatonin receptors and the circadian clock. Current studies on melatonin and PMS are not sufficient. For example, symptoms such as sleep disturbance, depressive mood, and cognitive impairment are not specific and can be easily misdiagnosed with other diseases. Based on previous studies, ovarian steroids seem not specific among PMS patients, and the effect of melatonin supplementation is not clearly clarified. From the view of molecular modulation, what’s the change and relationship between melatonin receptors and PMS are still unknown. As a consequence, studies on melatonin’s role in the female reproductive system should be augmented. Further research on the relationship between melatonin and PMS may focus on the perspectives described below. First, adequate animal models should be developed to unveil the underlying mechanisms of PMS. Recently, Bellofiore and his colleagues found that spiny mice exhibit PMS-like symptoms and can serve as a preclinical model of PMS ( 162 ). However, melatonin secretion patterns and rhythms between nocturnal animals and human beings are not similar, providing another impediment of melatonin-PMS interaction studies. Second, as functional magnetic resonance imaging reveals deficient positive emotion processing during the female luteal phase ( 163 ), functional imaging can be adopted to analyze brain activation patterns and neural circuit alterations in PMS. Third, melatonin’s modulation of the hypothalamus-pituitary-ovary (HPO) axis requires further investigation. Although current studies have shown that melatonin regulates estrogen and progesterone levels, since HPO dysfunction is characterized in PMS and regulated by the SCN, kisspeptin neurons and other endocrine factors, does melatonin participate in these regulatory effects? If it participates, what are the possible mechanisms and pathways? These questions should be taken into consideration in future research. Finally, pharmacological studies on melatonin receptor agonists and structural studies on MT1 and MT2 receptors should be conducted. To date, melatonin receptor agonists such as agomelatine and ramelteon are recommended for depression and insomnia treatments, respectively. However, these agonists are nonselective, making it difficult to target MT1 or MT2 receptors specifically to achieve satisfying therapeutic effects. Understanding structural differences between MT1 and MT2 receptors and their different affinities to some compounds may be the foundation of selective melatonin receptor agonist development and application.

JS contributed to the study concept and design. WY and JZ collected and sorted the literature. WY and YG drew pictures and tables. WY and JZ wrote the first draft. ZW and CD edited and approved the English version of the article. All authors contributed to the article and approved the submitted version.