Melatonin for Menopausal Sleep Disorders and Quality of Life

By Judith L. Balk, MD. Dr. Balk is Associate Professor, Magee-Women's Hospital, University of Pittsburgh; she reports no financial relationship to this field of study.

Sleep disruption in menopause is common. one-fourth to one-half of all women will note some sleep complaint during menopause, as compared to approximately 15% in the general population.1 Menopausal women are 3.4 times more likely to report trouble sleeping than premenopausal women, although there have been few documented polysomnographic changes associated with menopause.1 Aging itself appears to be a risk factor for changes in sleep studies. Three types of sleep disorders are associated with menopause: insomnia with depression, sleep-disordered breathing, and fibromyalgia.1 In addition, perimenopausal and postmenopausal women often have vasomotor symptoms contributing to disrupted sleep. A "domino hypothesis" has been proposed, in which vasomotor symptoms lead to disrupted sleep, which then leads to insomnia followed by depression.1 Clearly, intervening at an early stage in this "domino" scenario might be helpful in preventing insomnia-related depression.

The changing hormonal milieu in menopause may have direct effects on various components of sleep architecture.1 For instance, estrogen administration decreases sleep latency and the number of cyclic spontaneous arousals, and when women are in the lower estrogen phases of the menstrual cycle, the number of sleep arousals doubles. Progesterone appears to have two direct effects on sleep; the first is that progesterone is considered to be sedating because it is a GABA agonist; the second effect of progesterone is that it is a respiratory stimulant and has been used to treat mild obstructive sleep apnea.2 Thus, progesterone that is produced in the luteal phase may be protecting against sleep apnea; sleep apnea is more common postmenopausally, when no progesterone is produced by the ovary, than premenopausally. Cortisol and testosterone also may play a role in sleep architecture.

Melatonin

In addition to gonadal and adrenal hormones, melatonin also may play a role in sleep architecture in menopausal women. Melatonin secretion throughout the diurnal cycle is higher in younger people than in older adults.3 In addition, while melatonin overall decreases with age, there appear to be two specific and dramatic periods of reduction in melatonin levels in women: from age < 40 to 40-44 years of age, and from 50-54 to 55-59 years of age.4 Because melatonin levels appear to decrease prior to the onset of menopause, some investigators have suggested that melatonin may be linked to the initiation of menopause.4 The interactions between melatonin and estrogen are complicated. It is likely that changes in melatonin secretion affect sex steroids, but the converse probably does not occur.5 Postmenopausal women with insomnia generally have lower melatonin levels than postmenopausal women without insomnia. In addition, depressed patients have lower levels of melatonin compared with normal controls.6

The amino acid L-tryptophan is converted to serotonin and then to melatonin in the pineal gland.7 Melatonin synthesis follows a circadian rhythm, in which little melatonin is secreted during daylight hours. With the onset of darkness, melatonin synthesis and release begin. Melatonin levels peak between 2 a.m. and 4 a.m. Darkness is stimulatory and light is inhibitory to melatonin synthesis and release.5 Day-night light cycles modify the melatonin rhythm, and brief pulses of light of sufficient intensity and duration abruptly suppress melatonin production.5 Melatonin receptors exist in the brain and in peripheral tissues, such as the gut and ovaries, and blood vessels; melatonin likely has circadian rhythm, reproductive, and temperature regulation functions. In addition to receptor-mediated actions, it also has nonreceptor actions, such as being a potent scavenger of oxygen-centered free radicals and augmenting the immune response. Melatonin has been shown to regulate progesterone production via melatonin receptors in human granulosa-lutein cells.8 Melatonin's effects on perimenopausal symptoms may be related to a direct action of melatonin on the central nervous system, as opposed to the sex hormone pathway.9 Melatonin may play a role in inhibiting breast cancer, although evidence for this is indirect.5 Interestingly, melatonin can react with the GABA receptor in a benzodiazepine-like way.7 Rohr and Herold suggest that this interaction may help to explain melatonin's effects on mood improvement and pain reduction in fibromyalgia patients. Gabapentin, a GABA analogue, is used to treat menopausal hot flushes;10 it is possible that melatonin, via GABA-like effects, may be beneficial for perimenopausal and menopausal women.

Animal Research

Gonadal and adrenal hormones may act on different sites in the pineal gland and thus may affect melatonin in different ways.11 Both progesterone and estrogen receptors exist in the pineal gland in animals. In rats, melatonin synthesis and secretion is reduced during proestrus, when estradiol and progesterone levels are elevated. Antiestrogens reduce the nocturnal peak, whereas antiprogestogens increase it. In some animals, the secretion of melatonin from the pineal gland plays a major role in regulating reproductive physiology; in humans, these relationships are less clear.12

Human Research

A blinded clinical trial in Italy investigated 6 months of placebo or melatonin, 3 mg, in premenopausal, perimenopausal, and postmenopausal women with neurovegetative, sleep, and/or psychological symptoms.13 Randomization was not stated, nor was assignment allocation. The investigators noted that at 6 months, the placebo and melatonin groups differed in mood; 6.7% of melatonin-treated subjects reported continuing morning depression, compared to 21% of placebo-treated subjects (P < 0.05). The investigators also noted that 12 menopausal women (at 1 and 2 years after total cessation of menses) reported a reacquisition of normal menstrual cycles. The ages of these women were not stated. The investigators note that melatonin depressed the production of follicle stimulating hormone only in women with low melatonin levels at baseline. They postulate that melatonin "restores menstrual cyclicity and fertility in perimenopausal or menopausal women." More research must be done to fully investigate the hormonal effects of melatonin. Although not statistically significant, many women reported a tendency to amelioration of hot flushes and improvement in quality and duration of sleep.

Researchers in Pittsburgh conducted a pilot double-blind, placebo-controlled study in which perimenopausal women were randomized to melatonin (3 mg orally nightly) or placebo in a 3:1 ratio, results of which were presented in abstract form at Women's Health 2011: The 19th Annual Congress.14 Outcomes included Menopausal Quality of Life, sleep, and menstrual patterns, and results showed that melatonin significantly improved physical aspects of quality of life as measured by the Menopause-specific Quality of Life Questionnaire. Also, subjects in the melatonin group had significantly fewer menstrual periods over the 6-month study. Sleep quality did not differ significantly between groups, although subjects in the melatonin group thought that they were sleeping better and feeling better. Because melatonin is thought to directly increase progesterone production,8 improved sleep and fewer menstrual cycles would be biologically plausible.

One large study investigated a "prolonged-release melatonin formulation," in a dose of 2 mg.15 This medication was approved in Europe in 2007 for treatment of primary insomnia in patients ages 55 or older (limit was based on the known decrease in melatonin levels with age). A randomized, double-blind, parallel-group, placebo-controlled trial was conducted over roughly 30 weeks in 930 men and women aged 18-80 with primary insomnia. Two-thirds of the patients were female. Sleep latency was improved in the treatment group relative to placebo in those aged 55-80, but not in the whole group, which included younger patients. Other sleep, quality of life, and clinical status variables improved in the treatment group relative to placebo. No signs of tolerance were seen, and no withdrawal symptoms or rebound insomnia were detected. One patient in the melatonin group experienced palpitations, and this was assessed as possibly drug-related. Otherwise, the only adverse event that was deemed treatment-related was in a subject treated with placebo.

Safety

Theoretically, melatonin may have interactions with medications, botanicals, and supplements with antiplatelet/anticoagulant constituents and might increase the risk of bleeding in some people. For instance, there have been several case reports of excessive bleeding in patients taking warfarin and melatonin.16 Concomitant use with medications or botanicals that have sedative properties might enhance both the therapeutic and adverse effects of melatonin. When melatonin is administered in the morning, dizziness, drowsiness, and lack of alertness during the day have been reported.7 Based on the evidence, it is not clear if higher dosages have more side effects.

Conclusion

More research is necessary to fully delineate the indications for melatonin in perimenopausal and postmenopausal women. It may help with sleep issues, but evidence for this is limited. Short-term usage of melatonin is a rational therapeutic approach for the alleviation of insomnia and circadian phase disorders of peri- and postmenopausal women, as these periods of life are characterized by changes in sleep quality and circadian rhythms.5 The best effect of melatonin is shown when it is administered 6 hours before the natural peak7 that occurs between 2 a.m. and 4 a.m. Thus, administering melatonin between 8 p.m. and 10 p.m. would give the best results for sleep disorders. Dosages above 5 mg do not appear to be better than dosages between 0.5 mg and 5 mg.

Recommendation

Melatonin at dosages up to 5 mg may be helpful for perimenopausal and postmenopausal women with sleep disorders, although more research is necessary to delineate the indications, length of treatment, and dosage. Melatonin appears to be safe in most individuals, but more research is necessary to fully understand its side effect profile and contraindications.

References

1. Eichling P, Sahni J. Menopause related sleep disorders. J Clin Sleep Med 2005;1:291-300.

2 Empson J, Purdie D. Effects of sex steroids on sleep. Ann Intern Med 1999;31:141-145.

3. Iguchi H, et al. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Med 1982;55:27-29.

4. Vakkuri O, et al. Decrease in melatonin precedes follicle-stimulating hormone increase during perimenopause. Eur J Endocrin 1996;135:188-192.

5. Brzezinski A. Melatonin replacement therapy for postmenopausal women: Is it justified? Menopause 1998;5:60-64.

6. Parry B, et al. Increased melatonin and delayed offset in menopausal depression: Role of years past menopause, follicle-stimulating hormone, sleep end time, and body mass index. J Clin Endocrinol Med 2008;93:54-60.

7. Rohr U, Herold J. Melatonin deficiencies in women. Maturitas 2002;41(suppl 1):S85-S104.

8. Woo M, et al. Direct action of melatonin in human granulosa-luteal cells. J Clin Endocrinol Med 2001; 86:4789-4797.

9. Fideleff H, et al. Effect of melatonin on the basal and stimulated gonadotropin levels in normal men and postmenopausal women. J Clin Endocrinol Med 1976;42:1014-1017.

10. Reddy S, et al. Gabapentin, estrogen, and placebo for treating hot flushes: A randomized controlled trial. Obstet Gynecol 2006;108:41-48.

11. Manber R, Armitage F. Sex, steroids, and sleep: A review. Sleep 1999;22:540-555.

12. Reiter R. Melatonin and human reproduction. Ann Med 1998;30:103-108.

13. Bellipanni G, et al. Effects of melatonin in perimenopausal and menopausal women. Ann NY Acad Sci 2005;1057:393-402.

14. Kotlarczyk M, et al. The effects of melatonin on menstrual cycle and quality of life. Women's Health 2011: The 19th Annual Congress. Washington, DC.

15. Wade A, et al. Prolonged release melatonin in the treatment of primary insomnia: Evaluation of the age cut-off for short- and long-term response. Current Med Res Opin 2011;27:87-98.

16. Herxheimer A, Petrie K. Melatonin for the prevention and treatment of jet lag (Review). Cochrane Database Syst Rev 2002;2:CD001520.