Insomnia is a major complaint among menopausal and postmenopausal women, presumably due to decreased levels of estrogen and melatonin. As a woman approaches menopause, estrogen levels sharply decrease, while melatonin serum levels also decline, though in a more gradual course. These hormonal changes significantly impact sleep quality and contribute to various menopausal symptoms, including hot flashes, vaginal dryness, sexual dysfunction, mood disturbances, anxiety, and restlessness. This article explores the intricate relationship between melatonin, estrogen, and sleep disturbances during menopause, highlighting the latest research and potential treatments.
Hormonal Changes and Sleep Disturbances
Estrogen and Melatonin Decline
The menopausal transition is marked by a significant decline in estrogen levels. Estrogen, a crucial hormone for reproductive and overall health, plays a vital role in regulating sleep. Its decline leads to various symptoms that can disrupt sleep, such as hot flashes and night sweats. Simultaneously, melatonin levels also decrease, although more gradually. Melatonin, known as the sleep hormone, regulates the sleep-wake cycle and its reduction contributes to insomnia and other sleep disturbances.
Studies show that melatonin levels drop significantly during menopause, affecting sleep quality and duration. For instance, a study by Kravitz et al. (2003) found that postmenopausal women had significantly lower nighttime melatonin levels compared to premenopausal women. This decline in melatonin, combined with fluctuating estrogen levels, results in a higher prevalence of insomnia among menopausal women.
Menopause-Associated Sleep Disorders
Research indicates that menopause-associated sleep disorders can be categorized into three primary subtypes: insomnia with concurrent or developing depression, sleep-disordered breathing, and sleep disturbances in fibromyalgia. These conditions, influenced by melatonin levels and other hormonal factors, present unique challenges and require distinct therapeutic approaches.
Insomnia and Depression
Insomnia is often accompanied by depression during menopause. The hormonal changes, particularly the decline in estrogen and melatonin, contribute to mood disturbances and anxiety, exacerbating sleep problems. Studies have shown a strong correlation between menopause, depression, and insomnia. For example, Soares et al. (2001) reported that women experiencing menopause-related depressive symptoms also exhibited higher rates of insomnia.
Sleep-Disordered Breathing
Sleep-disordered breathing, including obstructive sleep apnea (OSA), is another common issue among menopausal women. The decline in estrogen and progesterone levels impacts the muscle tone of the upper airway, increasing the likelihood of airway collapse during sleep. This condition not only disrupts sleep but also leads to daytime fatigue and other health complications. A study by Young et al. (2003) found that postmenopausal women were twice as likely to suffer from sleep apnea compared to premenopausal women.
Sleep Disturbances in Fibromyalgia
Fibromyalgia, a condition characterized by widespread musculoskeletal pain, fatigue, and sleep disturbances, is also prevalent among menopausal women. The hormonal changes during menopause can trigger or worsen fibromyalgia symptoms, including poor sleep quality. Studies indicate that melatonin supplementation may help alleviate fibromyalgia-related sleep disturbances. For instance, a study by Citera et al. (2000) found that melatonin treatment improved sleep quality and reduced pain in patients with fibromyalgia.
Melatonin Rhythm and the Central Circadian Pacemaker
The Role of the Suprachiasmatic Nucleus (SCN)
The suprachiasmatic nucleus (SCN), located in the anterior hypothalamus, acts as the central circadian pacemaker, regulating the sleep-wake rhythm via the sympathetic and parasympathetic nervous systems. The SCN controls melatonin synthesis in the pineal gland through a neuronal pathway activated by norepinephrine released from postganglionic sympathetic fibers. Light exposure suppresses melatonin secretion, resetting the circadian pacemaker and directly inhibiting melatonin synthesis.
In the absence of light, the pineal gland secretes melatonin, which diffuses into the bloodstream and reaches various body tissues. Melatonin, an amphiphilic molecule, can enter all cells, including crossing the blood-brain barrier. The pineal gland is the primary source of circulating melatonin, although significant amounts are also produced in other organs, such as the gastrointestinal tract and retina. However, these extrapineal sources contribute minimally to circulating levels due to intracellular sequestration.
Light and Melatonin Secretion
Light exposure has a significant impact on melatonin secretion. The relationship between light and melatonin secretion has two aspects: the phasing of the circadian pacemaker via mechanisms of resetting and the direct photic suppression of melatonin secretion. Light at night can immediately suppress melatonin secretion through a photic turn-off mechanism, which is not equivalent to phase shifting but involves downregulation of the rate-limiting enzyme of melatonin synthesis, aralkylamine N-acetyltransferase (AANAT).
The suppression of melatonin by light has important implications for menopausal women experiencing sleep disturbances. Exposure to artificial light, especially blue light from electronic devices, can further disrupt melatonin production and exacerbate insomnia. Therefore, managing light exposure, particularly in the evening, is crucial for improving sleep quality.
Human Aging and Melatonin Secretion
Aging is typically associated with impairments in the circadian system and a decline in melatonin secretion. These changes, highly variable among individuals, can lead to sleep disturbances, nocturia, and other age-related symptoms. Early subclinical changes in the circadian system typically develop around midlife, while later deteriorations, often linked to neurodegenerative diseases such as Alzheimer’s, cause more pronounced disruptions in circadian phase relationships and melatonin levels.
Interindividual Variability
The interindividual variability in decreased melatonin levels is, at least partially, explained by the effects of various diseases and disorders on melatonin formation and secretion. These conditions include psychiatric disorders, pain, stress-related pathologies, heart diseases, type 2 diabetes, and certain cancers. Notably, these changes in melatonin are also observed in some menopause-related symptoms. For instance, depression, obstructive sleep apnea syndrome (OSAS), chronic obstructive pulmonary disease (COPD), and fibromyalgia are associated with decreased melatonin levels and altered secretion patterns.
Health Consequences of Decreased Melatonin Levels
The decline in melatonin levels during menopause can have various health consequences beyond sleep disturbances. Melatonin is known for its role in regulating sleep, but it also influences numerous physiological functions, including immune modulation, neuronal protection, pain management, bone health, and antioxidant defense.
Breast Cancer
Decreased melatonin levels have been linked to an increased risk of breast cancer. Night shift work, which suppresses melatonin, is associated with a higher incidence of estrogen-related breast cancer. In vitro studies suggest that melatonin has oncostatic properties, inhibiting cancer cell proliferation. Reduced urinary 6-sulfatoxymelatonin levels have been reported in postmenopausal women with breast cancer.
Endometrial Cancer
Melatonin may also have an oncostatic effect on endometrial cancer. Studies on estrogen receptor-positive endometrial adenocarcinoma cell lines indicate that melatonin inhibits cell proliferation via the MT2 receptor.
Bone Health
Melatonin positively affects bone density and strength, potentially reducing the risk of postmenopausal osteoporosis. Studies have shown that peri-menopausal women taking melatonin supplements exhibit improved markers of bone turnover. For example, a study by Kotlarczyk et al. (2012) found that melatonin supplementation improved bone health markers in perimenopausal women, suggesting its potential in preventing osteoporosis.
Treatment of Insomnia in Postmenopausal Women
Postmenopausal women often experience difficulty falling asleep, frequent awakenings, and early morning arousals. These sleep complaints can result from various factors, including hormonal changes, poor sleep hygiene, depression, primary sleep disorders, and comorbidities such as fibromyalgia.
Hormone Replacement Therapy
Hormone replacement therapy (HRT) with combinations of estrogen and gestagens is commonly used to treat menopausal sleep disturbances. HRT effectively suppresses vasomotor symptoms, which are a major cause of sleep disruption during menopause. Transdermal and gel preparations of gonadosteroids offer convenient alternatives to oral administration, providing consistent hormone levels and minimizing side effects.
Melatonin Supplementation
Melatonin supplementation is a popular alternative for managing sleep disturbances in postmenopausal women. Exogenous melatonin can improve sleep onset latency and overall sleep quality without causing a morning hangover or other significant side effects. Studies have shown that melatonin treatment can enhance mood and alleviate depression in insomniac postmenopausal women.
However, the efficacy of melatonin varies among individuals, and improvements in sleep maintenance are often moderate. Some studies suggest that low doses of melatonin (0.3-1.0 mg) are most effective, while others recommend doses up to 5 mg. Higher doses (50-100 mg) may be beneficial for individuals with metabolic syndrome, but more research is needed to support this assumption.
Melatonergic Drugs
Melatonergic drugs, such as ramelteon and agomelatine, have been developed to treat insomnia and related conditions. Ramelteon, a melatonergic receptor agonist, has been shown to increase total sleep time and sleep efficiency while reducing sleep onset latency. Agomelatine, which also has antidepressant properties, is effective in treating insomnia comorbid with depression. However, it carries a risk of hepatotoxicity, necessitating careful monitoring.
Conclusion
Insomnia is a significant concern for menopausal and postmenopausal women, often linked to hormonal changes, particularly decreases in estrogen and melatonin levels. Understanding the complex interplay between these hormones and sleep disturbances is crucial for developing effective treatments. Hormone replacement therapy, melatonin supplementation, and melatonergic drugs offer promising options for managing menopausal insomnia, but individual responses can vary. Ongoing research is essential to optimize treatment strategies and improve the quality of life for affected women.
APPENDIX 1 – MELATONIN
Melatonin is a hormone primarily secreted by the pineal gland, playing a key role in regulating the sleep-wake cycle. It has significant physiological and pharmacological functions, including neuroprotection and the control of neuronal plasticity. Melatonin secretion peaks during childhood and adolescence, reducing significantly with age, which can lead to altered sleep patterns and reduced neuronal plasticity.
Technical Data Sheet and Capabilities:
Chemical Properties:
- CAS Number: 73-31-4
- Molecular Formula: C13H16N2O2
- Appearance: Off white granular powder
Solubility:
- Soluble in water
Usage:
- Dietary supplements
- Food supplements
- Sleep aid, particularly for insomnia and jet lag
Dosage:
- Common dose: 2 mg once daily, 1-2 hours before bedtime
Safety Information:
- No specific uses advised against
- Not classified for reproductive toxicity
Analytical Methods:
- Quantitative Analysis: Reverse Phase HPLC
- Purity: ≥97%
Detailed Scheme Table:
| Parameter | Details |
|---|---|
| Chemical Name | Melatonin |
| CAS Number | 73-31-4 |
| Molecular Formula | C13H16N2O2 |
| Physical Appearance | Off white granular powder |
| Solubility | Soluble in water |
| Common Usage | Dietary supplements, sleep aid |
| Recommended Dosage | 2 mg once daily, 1-2 hours before bed |
| Safety Classification | No specific reproductive toxicity |
| Analytical Methods | Reverse Phase HPLC |
| Purity | ≥97% |
To naturally increase melatonin levels through your diet, you can incorporate various foods rich in this hormone. Here are some of the best sources:
- Tart Cherries: These are one of the most well-known sources of melatonin. Both the fruit and its juice can help improve sleep quality and duration. Tart cherry juice is particularly potent.
- Eggs: These are not only versatile and nutritious but also a good source of melatonin and tryptophan, which the body converts into melatonin and serotonin.
- Milk: A traditional sleep aid, milk contains melatonin and tryptophan. Warm milk before bed can promote better sleep due to its melatonin content .
- Fish (especially fatty fish like salmon): Rich in melatonin, omega-3 fatty acids, and vitamin D, fatty fish like salmon can help regulate sleep patterns and improve sleep quality.
- Nuts (especially pistachios and walnuts): Pistachios have one of the highest melatonin contents among nuts, while walnuts also contribute beneficial levels. These nuts are also rich in vitamins and minerals that support overall health .
- Goji Berries: Known for their high antioxidant levels, goji berries also contain melatonin and can help improve sleep quality .
- Rice: Particularly pigmented varieties like red rice are high in melatonin. Including these in your diet can naturally boost melatonin levels .
- Grapes: Both fresh grapes and wine made from grapes contain melatonin, the latter benefiting from additional melatonin synthesized during fermentation.
- Oats: Commonly used in breakfast foods, oats are a good source of melatonin and other essential nutrients that support sleep .
- Pineapple: This tropical fruit can increase melatonin production in the body, contributing to better sleep .
Incorporating these foods into your diet can help naturally boost your melatonin levels, promoting better sleep and overall health. Make sure to consume these foods a few hours before bedtime to maximize their sleep-inducing effects.
reference : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611767/
