**4. Melatonin lipid metabolism**

A growing number of evidences are emerging, which point to melatonin involvement into lipid metabolism. The study of H. Tamura was devoted to melatonin influence on lipid metabolism among women in perimenopause and postmenopause. A negative correlation was established between nocturnal melatonin and total cholesterol level, low-density lipoprotein, and positive correlation with high-density lipoprotein. No correlation was found between nocturnal melatonin and triglyceride level in blood. These findings show that melatonin drug prescription may represent a new approach to the correction of lipid metabolism and prevention of cardiovascular diseases during perimenopause and postmenopause [23]. Other scientists determined that melatonin improves lipid profile (leads to a reduced level of low-density lipoprotein) and fulfills antioxidant protection [24].

Under a study led by L.I. Maltseva [25], scientists analyzed melatonin role in the development of climacteric syndrome and its effectiveness for treating pathological climacterium. Russian scientists established that the level of 6-sulfatoxymelatonin in a 24-h urine among patients with severe climacteric syndrome amounts to 35.09 ± 3.5 ng/ml, medium severity (44.01 ± 7.92 ng/ml), and mild climacteric syndrome (45.91 ± 12.42 ng/ml) (1.7 times lower as compared to women in good health). Accordingly, secretory function of hypophysis is altered in various ways. Women with low level of 6-sulfatoxymelatonin in a 24-h urine show significant growth of both gonadotropic hormones—follicle-stimulating and luteinizing hormones—in a proportional way. A research showed that women had a high level of catecholamines (adrenaline and noradrenaline) with its degree being dependent on climacteric syndrome severity. It was also determined that women in perimenopausal age have increased the level of atherogenic fractions of blood lipids on the background of lower melatonin level.

Scientists came to the conclusion that melatonin acts as a modifier of alterations which occur with the development of climacteric disorders and influence hormonal, mediating, and biochemical indicators of the female body. Women with mild climacteric syndrome taking 3 mg of melatonin per day as monotherapy demonstrated during the repeated evaluation of clinical, hormonal, and biochemical indicators after 1 month a positive dynamics of all indicators. The blood hormone level was close to reference values, follicle-stimulating hormone level dropped by 2.29 times, luteinizing hormone level by 2.1 times. Values of melatonin sulfate in a 24-h urine grew by 2.64 times and were close as never to the reference values 27.95 ± 7.92…73.95 ± 24.85 ng/ml. However more significant alterations were noted for the severe climacteric syndrome without any side effects when melatonin treatment and menopause hormonal therapy were used together [25].

## **5. Menopause and sleep disturbance**

Japanese scientists stated that estradiol level was firmly higher among women that worked night shifts and went to sleep later than 1 a.m. as compared to women that slept at night, with the level of serum testosterone and DHEA-sulfate unaffected, while 6-sulfatoxymelatonin concentration in urine was lower among the first group patients. Similar hormonal disruptions among postmenopausal women experiencing sleep disorder represent serious risk factors of breast cancer [26]. Singapore Chinese Health Study (2008) also showed that among women in postmenopause, the risk of breast cancer gets lower when sleep duration increases (*p* = 0.047). When sleep duration exceeds 9 h, a relative risk equals to 0.67 (95% confidence interval 0.4–1.1) as compared to women with a sleep duration of 6 h or less. At that, melatonin level was higher by 42% when sleep duration was 9 h or more. Such pattern was registered for women with normal weight (body mass index of 23.2 kg/m), *p* = 0.024 [27]. American scientists proved through a largescale

**41**

*Role of Pineal Hormone Melatonin in a Woman's Life: From Conception to Decline of Life*

prospective analysis that among women with 6-sulfatoxymelatonin content within the upper quartile, there were fewer with invasive breast cancer than among those whose values were within the bottom quartile [28]. It was established that the increased concentration of 6-sulfatoxymelatonin in the morning urine portion was statistically related to a lower risk of breast cancer (ratio of chances for upper and lower quartiles of 6-sulfatoxymelatonin level 0.62; 95% confidence interval

C.G. Harrod and his colleagues made an assumption that a growing risk of cerebrovascular disease registered among menopausal women can be to some extent explained by changes in the level of circulating melatonin and estrogens and their modulating influence on biologic activity of endothelial cells, including vascular tone regulation, leukocytes adhesion, and angiogenesis. This hypothesis is confirmed by numerous studies demonstrating the braking effect of melatonin and

estrogens on vessel tone, neuroprotection, and expression of receptors [30].

Increased melatonin secretion in the morning is more typical for menopausal patients with depression than women in good health. Moreover, menopause duration, level of the follicle-stimulating hormone, sleep end time, and body mass index may lead to alterations in melatonin secretion when suffering from depression

At present a relation between melatonin and skeleton is known. Melatonin may produce an effect on bone tissue which manifests itself in bone tissue formation with osteoblasts and/or hindering bone resorption with osteoclasts. The study of K. Satomura et al. [31] confirms the melatonin (*Mel1*) receptor expression in human osteoblasts and tendency of its level reduction with aging. It is also demonstrated that melatonin can have a boosting effect on proliferation and differentiation of human osteoblasts [32]. Through a controlled randomized trial (2012), exogenous melatonin effect on bone tissue density was revealed. Bone tissue condition was controlled in two ways—bone tissue density estimation and bone marker determination. There was no considerable improvement noted in terms of bone tissue density in T points or as compared with placebo. An average change in the activity of bone resorption marker, N-telopeptide (NTX), in this study did not differ much inside and between the groups. Similarly, the average change in the activity of bone formation marker, osteocalcin, did not show any remarkable differences either inside a group or between groups. However, NTX to osteocalcin ratio followed a downward trend among the women who took melatonin as compared to placebo. It is quite important because among menopausal women, this ratio is known to increase so that osteoclasts activity outstrips osteoblast activity, which leads to a loss of bone mass. Probably, decreased level of nocturnal melatonin that occurs during a menopause causes hormonal unbalance and perimenopause symptoms, including the loss in bone mass. These data prove that melatonin intake may enable the balancing of bone resorption and formation processes, potentially preventing fast

Melatonin inhibits resorption activity by reducing RANKL-mediated osteoclastogenesis and therefore decreases bone resorption. Melatonin also protects from losing bone mass induced by free radicals, which occurs in the case of extreme bone resorption, due to its powerful antioxidative properties [34, 35]. In addition to its direct effect on the bone tissue, melatonin can produce an indirect influence on bone metabolism through the hypothalamus-pituitary axis, by suppressing levels of

*DOI: http://dx.doi.org/10.5772/intechopen.88999*

0.41–0.95; *p* = 0.004) [29].

during a menopause [8].

**6. Melatonin effects on bone metabolism**

loss of bone mass attributed to a menopausal period [33].

*Role of Pineal Hormone Melatonin in a Woman's Life: From Conception to Decline of Life DOI: http://dx.doi.org/10.5772/intechopen.88999*

prospective analysis that among women with 6-sulfatoxymelatonin content within the upper quartile, there were fewer with invasive breast cancer than among those whose values were within the bottom quartile [28]. It was established that the increased concentration of 6-sulfatoxymelatonin in the morning urine portion was statistically related to a lower risk of breast cancer (ratio of chances for upper and lower quartiles of 6-sulfatoxymelatonin level 0.62; 95% confidence interval 0.41–0.95; *p* = 0.004) [29].

C.G. Harrod and his colleagues made an assumption that a growing risk of cerebrovascular disease registered among menopausal women can be to some extent explained by changes in the level of circulating melatonin and estrogens and their modulating influence on biologic activity of endothelial cells, including vascular tone regulation, leukocytes adhesion, and angiogenesis. This hypothesis is confirmed by numerous studies demonstrating the braking effect of melatonin and estrogens on vessel tone, neuroprotection, and expression of receptors [30].

Increased melatonin secretion in the morning is more typical for menopausal patients with depression than women in good health. Moreover, menopause duration, level of the follicle-stimulating hormone, sleep end time, and body mass index may lead to alterations in melatonin secretion when suffering from depression during a menopause [8].
