Women have a greater risk for developing insomnia than men [1] [2] . Studies have shown that 25% of women aged between 50 and 64 years report sleep problems, and 15% of those report severe sleep disturbance that has a substantial effect on their quality of life [3] . Data from the Study of Women’s Health Across the Nation (SWAN) indicate that approximately 70% of women report Vaso Motor Symptoms (VMS) at some point during the menopausal transition. Approximately 30% to 40% of midlife women report sleep disturbance [4] .

Women frequently cite VMS at night as the source of this sleep disturbance [5] , and epidemiologic investigations using questionnaire measures of VMS and sleep show VMS to be a consistent correlate of reported sleep disturbance. Troubled sleeping seems to be worse in postmenopausal compared with premenopausal women, and significantly worse in surgically postmenopausal compared with naturally postmenopausal women.

Although most epidemiologic studies have found increased reports of sleep disturbance at menopause, this has not been confirmed by laboratory sleep studies. Thus, complaints of poor sleep in menopausal women could also reflect an age-related increase in the prevalence of primary sleep disorders. It has been reported that primary sleep disorders (apnea and restless legs syndrome) are common in this population, however, amelioration of hot flashes may reduce some complaints of poor sleep but will not necessarily alleviate underlying primary sleep disorders [6] .

Estrogen and progesterone are involved in a number of brain functions, including sleep [3] . Sex steroid receptors are found in multiple brain areas that are involved in sleep. However, the relationship between hormone replacement therapy (HRT) use and sleep quality is controversial. A recent study showed that stopping HRT led to a moderate increase in sleep difficulties in women aged 45 - 80 years. Use of HRT led to self-reported improved sleep in a large prospective and omised placebo-controlled study of older postmenopausal women [5] .

Other hormones that also may play a role in the regulation of sleep include cortisol and melatonin. Circadian rhythm training and maintaining a fixed sleep-wake cycle with adequate sleep duration is an important strategy in improving sleep quality. Melatonin assists in establishing and maintaining the circadian rhythm and sleep, as discussed in details in the next paragraphs.

In humans, the circadian rhythm of melatonin release from the pineal gland is highly synchronized with the habitual hours of sleep, and the daily onset of melatonin secretion is well correlated with the onset of the steepest increase in nocturnal sleepiness (“sleep gate”) [7] [8] . Serum melatonin levels were reported to be significantly lower (and the time of peak melatonin values was delayed) in elderly subjects with insomnia compared with age-matched subjects with no insomnia [9] . Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age [10] [11] . However existing studies on the hypnotic efficacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration. Adding to this complexity, there continues to be considerable controversy over the meaning of the discrepancies that sometimes exist between subjective and objective (polysomnographic) measures of good and bad sleep [12] .

Thus, attention has been focused either on the development of more potent melatonin analogs with prolonged effects or on the design of prolonged-release melatonin preparations [13] [14] . The MT [1] and MT [2] melatonergic receptor ramelteon [15] [16] was effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients [17] . The melatonergic antidepressant agomelatine, displaying potent MT [1] and MT [2] melatonergic agonism and relatively weak serotonin 5HT(2C) receptor antagonism [18] , was found effective in the treatment of depression associated insomnia [19] -[22] . Other melatonergic compounds are currently developed [23] [24] .

Melatonin’s two well-established physiological effects—promotion of sleep and entrainment of circadian rhythms—are both mediated by two specific receptor proteins in the brain, and not by the gamma-aminobutyric acid (GABA) receptors through which most hypnotic agents act. This difference probably explains why, unlike the GABA-agonist drugs, which are true “sleeping pills”, exogenous melatonin does not suppress rapid eye movement (REM) sleep nor, in general, affect the distribution of sleep stages [25] .

Measurements of melatonin in body fluids in elderly subjects have convincingly demonstrated an age-related impairment of nocturnal pineal melatonin synthesis [26] -[28] . Melatonin production declines with menopause and increasing age, and is lower in middle-aged and women with insomnia [29] . Several studies have shown the importance of melatonin both for the initiation and for maintenance of sleep [30] . In all diurnal animals and in human beings, the onset of melatonin secretion coincides with the timing of increase in nocturnal sleep propensity [31] .

In 2005 a meta-analysis [32] of 17 studies, involving 284 subjects, that satisfied inclusion criteria demonstrated a significant decrease in sleep latency and significant increases in sleep efficiency and total sleep duration. The inclusion criteria were that a study include at least six subjects, all adults, be randomized and doubleblinded, involve placebo-controlled clinical trials, and use objective measures of sleep evaluation. Studies could utilize crossover or parallel group designs; however, case reports were excluded. Statistical significance was obtained in spite of considerable variations among the studies in melatonin doses and routes of administration, the general health of the subjects, and the measures used to evaluate sleep.

The effects of exogenous melatonin on sleep have been examined under three types of experimental conditions in relation to the onset or offset of endogenous melatonin secretion.

In some studies, the hormone was administered during the daily light period, such that blood melatonin levels would be transiently elevated but would then return to baseline before the initiation of nocturnal melatonin secretion. Such experiments were used to demonstrate that melatonin decreases sleep latency at any time in the afternoon or evening, and that this effect is independent of an action on sleep rhythms (since no treatment can immediately shift the phase of a circadian rhythm by 8 - 10 hr).

In others, the hormone was given close enough to the onset of darkness for blood melatonin levels to still be elevated when nocturnal melatonin secretion started. The period during which plasma melatonin levels were continuously elevated would thus be prolonged. Such experiments reflected the use of melatonin to decrease sleep latency and maintain continuous sleep in, for example, a shift-worker or eastbound world traveler who needed to start sleeping earlier.

In yet others, the hormone was given at the end of the light period to older insomniacs with low night-time plasma melatonin levels. The intent was to prolong the portion of the night during which their plasma melatonin concentrations would be in the same range as those of noninsomniac young adults.

In all these situations, oral melatonin decreased sleep latency and, when tested, increased sleep duration and sleep efficiency. A 0.3 mg dose was either as effective as, or more effective than, [25] higher doses, particularly when the hormone was administered for several days. This dose had no effect on body temperature, affirming that, while pharmacologic doses can cause hypothermia, melatonin’s ability to promote sleep is not mediated by such a change, as had been suggested. The hormone had no consistent effect on sleep architecture (e.g., REM time). Its effects differed from those of most hypnotic drugs, since after receiving melatonin, subjects could readily keep from falling asleep if they chose so, and their cognitive abilities the next morning were unchanged or improved.

In a study of 30 people [25] who were 50 yr old or older and did or did not suffer from clinically significant insomnia (i.e., sleep efficiencies of 70% - 80% in the insomniacs vs. 92% in controls), melatonin was found to produce statistically and clinically significant improvements in sleep efficiency among insomniacs.

In yet another meta-analysis [33] published at the same year (2005), the authors found that melatonin decreased sleep onset latency (−11.7 minutes; 95% confidence interval [CI]: −18.2, −5.2); it was decreased to a greater extent in people with delayed sleep phase syndrome (−38.8 minutes; 95% CI: −50.3, −27.3; n = 2) compared with people with insomnia (−7.2 minutes; 95% CI: −12.0, −2.4; n = 12). The former result appears to be clinically important. However they conclude that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less) but that there was evidence to suggest that melatonin was effective in treating delayed sleep phase syndrome with short-term use.

A meta-analysis published in 2009 [34] focused on exogenous melatonin for sleep problems in individuals with intellectual disability. Nine studies (including a total of 183 individuals with intellectual disabilities) showed that melatonin treatment decreased sleep latency by a mean of 34 minutes (p < 0.001), increased total sleep time by a mean of 50 minutes (p < 0.001), and significantly decreased the number of wakes per night (p < 0.05). The authors concluded that melatonin decreases sleep latency and number of wakes per night, and increases total sleep time in individuals with intellectual disabilities.

Although in all the above studies about 30% - 50% of the participants were women the issue of menopauseassociated insomnia was not specifically addressed.

Because melatonin has a short half-life (<30 min), its efficacy in promoting and maintaining sleep has not been uniform in the studies undertaken so far. Thus, the need for the development of prolonged release preparations of melatonin or of melatonin agonists with a longer duration of action on sleep regulatory structures in the brain arose [35] .

In accordance with this idea slow release forms of melatonin were developed [13] (e.g., Circadin^R, a 2-mg preparation developed by Neurim, Tel Aviv, Israel, and approved by the European Medicines Agency in 2007). Their efficacy in treatment of sleep disorders in various populations were recently reported [36] .

Also recently, a small series of peri-menopausal women with insomnia treated with mirtazapine followed by prolonged-release melatonin, was published [37] . The author reported that sleep quality ratings improved significantly (by 103% on average) during combined mirtazapine and prolonged release melatonin (Circadin^R) intake and 180% during subsequent intake of prolonged-release melatonin alone or together with very low doses of mirtazapine. Well-being significantly improved by 83% during the treatment. No adverse events were reported.

A “sleep-switch” model to describe the regulation of sleep wakefulness was originally proposed by Saper and his colleagues [38] [39] . It consists of “flip-flop” reciprocal inhibitions among sleep-associated activities in the ventrolateralpreoptic nucleus and wakefulness-associated activities in the locus coeruleus, dorsal raphe, and tuberomammilary nuclei. The SCN has an active role both in promoting wakefulness as well as in promoting sleep, and this depends upon a complex neuronal network and a number of neurotransmitters released (GABA, glutamate, arginine vasopressin, somatostatin, etc.) [40] [41] .

The high density of melatonin receptors in the hypothalamic suprachiasmatic nuclei (SCN) [42] [43] may suggest that melatonin affects sleep and the sleep-wakefulness cycle by acting on these receptors. Thus, the need arose for the development of melatonin receptors agonists with a longer duration of action, and hopefully more potent in affecting sleep quality. The melatonin analogs ramelteon, agomelatine, tasimelteon, and TK-301 are examples of this strategy.

The data presented above clearly indicate that exogenous melatonin and its various analogs promote and maintain sleep. However, there is inconsistency and discrepancy among the large number of reports regarding the degree of efficacy and the clinical significance of these effects. The results of endogenous melatonin’s action in insomnia have not been consistent probably because the studies described in existing publications on melatonin’s efficacy have utilized different inclusion and exclusion criteria, different outcome measures to evaluate insomnia, different doses of the hormone, and different routes and timing of its administration. There also continues to be considerable controversy over the meaning of the discrepancies that sometimes exist between subjective and objective (polysomnographic) measures of good and bad sleep. Adding to this complexity is melatonin’s short half-life and ready metabolism after oral administration of fast release preparations. Hence, prolonged released melatonin preparations and melatonin agonists were introduced and have shown good results in treating insomnia.

It should be noted that very recently an official regulatory—the European Food Safety Authority (EFSA)— has evaluated the available evidence that melatonin can reduce the time it takes for normal sleepers and patients with insomnia to fall asleep [94] . It concluded that there is evidence that “a cause and effect relationship exists between the consumption of melatonin and reduction of sleep onset latency···”, and that “···1 mg of melatonin should be consumed close to bedtime···”.

Also, a recent consensus of the British Association for Psychopharmacology on evidence-based treatment of insomnia, parasomnia, and circadian rhythm sleep disorders concluded that melatonin is the first-choice treatment when a hypnotic is indicated in patients over 55 yr [95] .

These recommendations also apply for peri/post-menopausal women who suffer from insomnia. However, further investigations by randomized controlled studies to evaluate the efficacy of these interventions in this specific sub-population are warranted.