*2.3.2 Menopausal hormone therapy-related lipid metabolism*

Prevention of weight gain and lipid metabolic disorder is important components in the healthcare of postmenopausal women. Although the latest guideline from IMS indicated that MHT may ameliorate perimenopausal intra-abdominal fat accumulation, whether the MHT might maintain the lipid level during menopause transition has not been mentioned [21].

Numerous studies have attempted to understand the metabolic consequences of MHT use and define the effects of different MHT regimens. Major studies have consistently found MHT decrease LDL-C, TC and lipoprotein (a) levels; however, findings regarding TG and HDL-C levels have been inconsistent [45, 54–57]. Godsland reviewed the effect of different MHT regimens, estrogen alone, estrogen plus progestogen, raloxifene, or tibolone on plasma lipid and lipoprotein levels and found estrogen alone raise HDL-C and lower LDL-C and TC. Oral and transdermal estrogen had opposite effect on TG. The increases in HDL-C and TG when using estrogen alone were opposed according to the additional progesterone type. Specifically, effects arranged from the least to the greatest are dydrogesterone, medrogestone, progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate [58]. Stevens et al. suggested that MHT-related metabolic pathways is linked to multiple cellular processes, and the different MHT regimens might lead to distinct intracellular signal transduction events which contributed to the disparate risks for some diseases, e.g. CVD and cancer, in menopausal women with MHT [59].

In conclusion, different MHT regimens have different effects on lipid metabolism, exerting favorable and unfavorable changes. The choice for a particular regimen should consider individual demands, indications, complications, and lipid profile.

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

3.5 versus 4.2% and 6.2 versus 9.5%, respectively [33, 34].

by 24.7% with the dosage of 1.25 mg [31].

glucose level [35].

**therapy**

HDL-C [43].

glycometabolism [36].

*2.3.1 Lipid metabolism at menopause*

promotes insulin resistance. In one study, insulin tolerance test was undertaken following the estrogen replacement using conjugated equine estrogen. *K* value indicating insulin sensitivity increased by 25% with the dosage of 0.625 mg but decreased

Borissova et al. found that estrogen in MHT can promote insulin secretion after glucose administration, improve insulin sensitivity, and correct fasting hyperinsulinemia in postmenopausal women with Type 2 diabetes [32]. Two large randomized, double-blind trials also found that estrogen replacement significantly reduced the incidence of diabetes compared with the control group, the incidence rates were

However, some scholars believe that estrogen is unfavorable for glycometabolism in view that high level of estrogen could result in a decrease in glucose tolerance in oral contraceptives users. Studies also showed that estrogen, when given beyond its physical dosage, induced the glucocorticoid secretion and thus increased the blood

Lack of standardization for insulin sensitivity measurement, differences in the studied population, as well as types and routes of administration of hormone therapy may contribute to the discrepancies of effects of estrogen replacement on

**2.3 The influence of menopause on lipid metabolism and menopausal hormone** 

It is well known that estrogen has a significant effect on modulate lipid metabolism. A variety of research show that total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) increased in perimenopausal women, while menopause-related alternation in highdensity lipoprotein cholesterol (HDL-C) is inconsistent [1, 37–42]. Some studies reported a significant reduction, others found an increase in menopausal transition, and rest showed no changes in HDL-C, which El Khoudary has suggested that menopause-related alterations may influence other metrics of HDL that could not be fully reflected by just the cholesterol contents of HDL particles as measured by

The underlying mechanisms that estrogen and lipid interact at a molecular level to contribute to the risk of CVD are not clear. It has been reported that estrogenrelated receptor γ (ERRγ) regulates hepatic TG metabolism through the action phospholipase A2G12B [44], and polymorphic hepatic lipase is associated with estrogen modulate lipolysis of TG [45]. Della Torre et al. showed that liver ERα activity was essential for balanced lipid and TC metabolism, lack of ERα might lead to hepatic fat accumulation and nonalcoholic fatty liver disease [46]. Enza Distefano et al. suggested that estrogen activates the expression of LDL-receptor gene in HepG2 cells by tyrosine kinase signaling pathway [47]. Several research studies have suggested that estrogen can reduce circulating LDL-C but not cholesterol synthesis by downregulation of hepatic and plasma PCSK9, which is a suppressor of LDL receptors, in both animals and humans [48, 49]. Liu et al. reported that estrogen antagonizes oxidized LDL-induced secretion of macrophage matrix metalloproteinase-12 (MMP12,) and arterial stiffness that prevent from atheroscle-

Recent studies of our group have linked glycerol channel aquaporin 7 (AQP7) to protective effect of estrogen against body fat redistribution and hepatic steatosis in

**102**

rosis in women [50].

#### **2.4 Role of nonsex hormones in energy metabolism during menopausal transition**

#### *2.4.1 Role of leptin in energy metabolism at menopause*

Leptin is a protein hormone encoded by obese genes and secreted by adipose tissue. It has two effects on energy metabolism: on the one hand, it causes weight loss mainly by suppressing appetite. On the other hand, it has a number of effects on peripheral tissues: it can regulate energy balance by reducing lipid release into the blood circulation, reducing the output of triglycerides in target cells, and reducing the newly formed apolipoprotein B, which reduces the production of chylomicrons and low-density lipoprotein and increases apoA1, apoA IV, and apoE [60]. In obese people, the serum concentration of leptin is significantly elevated, which may be the result of leptin resistance [61]. At the same time, leptin plays a special role in maintaining normal reproductive function. The maintenance of human reproductive function requires adequate nutrition and storage of metabolic fuels, and leptin is a messenger with this signal [62, 63]. People who are emaciated lack such a signal.

In the peri-menopausal obesity, the role of leptin is still not clear. Several studies have found that the leptin level in the obese women was significantly higher than that in the nonobese women, but there is no significant difference in serum leptin levels pre and post menopause [64], and menopause does not significantly affect leptin production. Serum leptin levels were significantly positively correlated with BMI and waist circumference [65].

Moreover, in the studies of leptin level in different sexes, it was found that perimenopausal women had significantly higher level of leptin than men (even after adjusting for differences in male and female body weights) [66]. In the relationship between leptin and fat mass, it is different from gender. On the one hand, it is because of the inhibitory effect of androgen in blood on leptin. On the other hand, the difference in the amount of leptin in different fat distributions may also play a role. In fact, subcutaneous fat expresses more leptin mRNA than visceral fat [67], while male subcutaneous fat is less than female, so adipose tissue in males may produce less leptin than female adipose tissue. This can explain the difference in fat content in different genders, but it cannot explain that women before and after menopause have different fat distributions but have similar leptin levels. Kastin et al. studied the transfer of peptides from the blood into the brain in mice after ovariectomy and found that the transport of leptin into the brain was lower than that before ovariectomy [68]. Thus, they suggested that the weight gain caused by the loss of ovarian function in mice might be related to the decrease in leptin transported into the brain.

#### *2.4.2 Role of growth hormone in energy metabolism at menopause*

Growth hormone (GH) levels are lower in postmenopausal women than that in premenopausal women. Postmenopausal women have changes in body weight and body fat distribution, which may also be caused by changes in growth hormone axis function [69]. Snel et al. found that the fat mass in GH-deficient adults increased, and lean mass decreased [70], and this change could be reversed after supplementation with GH, thus confirming the importance of GH in regulating fat content.

GH regulates body weight through the hypothalamic-pituitary axis. Two peptides, growth hormone releasing hormone (GHRH) and growth hormone release inhibiting hormone (GHRIH), secreted by the hypothalamus, activate and inhibit the release of pituitary GH. The stress response of GH to GHRH in postmenopausal women decreases [71]. This response is similar to that in obese and elderly population; MHT supplementation in postmenopausal women can

**105**

*Ovarian Hormonal Change-Related Energy Metabolism and Obesity in Menopausal Women*

reconstitute GH response to GHRH. This shows that the neuroendocrine release of GH plays an important role in the control of neutral steroid hormones. On the other hand, high GH concentration may have exerted negative feedback by hypothalamic GHRIH [72]. The use of arginine in postmenopausal women does reconstitute the response of GH to GHRIH [73], which has nothing to do with BMI [71]. Therefore, we can assume that obesity, menopause, and aging are the characteristics of normal neuroendocrine changes caused by excessive effects of GHRIH, but the intrinsic

Incidence of overweight and obesity is increased in perimenopausal and menopausal women, which is an important public health concern. One of the reasons for increasing obesity during the menopausal transition is the increase in food intake. A combination of biological and psychological factors exerts potent influence on the

Women during the menopausal transition had decreased estrogen. Estrogen participates in the regulation of energy homeostasis, as evidenced by an increase in food intake and obesity in ovariectomized rats. In concordance, clinical evidence showed that hunger, desire to eat, and prospective food consumption are all increased during the menopausal transition, while fasting fullness is decreased. This trend persisted in the later postmenopausal years [74]. However, both animal and human studies indicate that overeating due to the lack of estrogen can be

Control of appetite is mainly performed in the hypothalamus of the central nervous system. Located in this region are arcuate, ventromedial, and paraventricular nuclei. Two major populations of arcuate neurons influence food intake in opposite directions. Neurons that extend projections to the lateral hypothalamic area express neuropeptide Y and Agouti-related peptide, which stimulate food intake and decrease energy expenditure. In other words, they extend orexigenic effects. Other arcuate neurons extend projections to the paraventricular nuclei and express proopiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART), which inhibit food intake and increase energy expenditure. Therefore, they extend anorexigenic effects [76, 77]. Estrogen acts as both a direct and an indirect control of appetite and food intake, modulating both anorexigenic and orexigenic signals in hypothalamus [78]. Estrogen regulates the function of the hypothalamic nuclei through complex processes. While ERα is abundantly expressed in the rodent brain in ventromedial, arcuate, and paraventricular and the medial preoptic area, ERβ expression is significantly lower [79]. Estrogens directly act on POMC neurons and regulate their cellular activity. ERα mRNA level in arcuate POMC neurons fluctuates over the course of the menstrual cycle, with the most dramatic increase on the day of proestrus, when E2 concentration is the highest [77]. In concordance, Xu et al. demonstrated that hypothalamic-specific deletion of ERa in steroidogenic factor-1 (SF1) neurons reduces energy expenditure. Deletion of ERa in POMC neurons alone increases appetite. Simultaneous deletion of ERa in POMC and SF1 neurons can add up these two effects and lead to hypometabolism and hyperphagia [80]. Peptidergic systems known to regulate ingestive behavior include ghrelin, neuropeptide Y (NPY), and melanin-concentrating hormone (MCH). Ghrelin peptide is a hunger-stimulating hormone, which is not only produced in the stomach by parietal cells but also produced in different areas of the hypothalamus,

*DOI: http://dx.doi.org/10.5772/intechopen.89336*

**2.5 Dietary intake at menopause**

regulation of appetite and food intake.

*2.5.1 Estrogen and the central control of appetite*

ameliorated by estrogen replacement therapy [75].

relationship between them remains to be further studied.

*Ovarian Hormonal Change-Related Energy Metabolism and Obesity in Menopausal Women DOI: http://dx.doi.org/10.5772/intechopen.89336*

reconstitute GH response to GHRH. This shows that the neuroendocrine release of GH plays an important role in the control of neutral steroid hormones. On the other hand, high GH concentration may have exerted negative feedback by hypothalamic GHRIH [72]. The use of arginine in postmenopausal women does reconstitute the response of GH to GHRIH [73], which has nothing to do with BMI [71]. Therefore, we can assume that obesity, menopause, and aging are the characteristics of normal neuroendocrine changes caused by excessive effects of GHRIH, but the intrinsic relationship between them remains to be further studied.

#### **2.5 Dietary intake at menopause**

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

*2.4.1 Role of leptin in energy metabolism at menopause*

BMI and waist circumference [65].

transported into the brain.

*2.4.2 Role of growth hormone in energy metabolism at menopause*

**2.4 Role of nonsex hormones in energy metabolism during menopausal transition**

Leptin is a protein hormone encoded by obese genes and secreted by adipose tissue. It has two effects on energy metabolism: on the one hand, it causes weight loss mainly by suppressing appetite. On the other hand, it has a number of effects on peripheral tissues: it can regulate energy balance by reducing lipid release into the blood circulation, reducing the output of triglycerides in target cells, and reducing the newly formed apolipoprotein B, which reduces the production of chylomicrons and low-density lipoprotein and increases apoA1, apoA IV, and apoE [60]. In obese people, the serum concentration of leptin is significantly elevated, which may be the result of leptin resistance [61]. At the same time, leptin plays a special role in maintaining normal reproductive function. The maintenance of human reproductive function requires adequate nutrition and storage of metabolic fuels, and leptin is a messenger with this signal [62, 63]. People who are emaciated lack such a signal. In the peri-menopausal obesity, the role of leptin is still not clear. Several studies have found that the leptin level in the obese women was significantly higher than that in the nonobese women, but there is no significant difference in serum leptin levels pre and post menopause [64], and menopause does not significantly affect leptin production. Serum leptin levels were significantly positively correlated with

Moreover, in the studies of leptin level in different sexes, it was found that perimenopausal women had significantly higher level of leptin than men (even after adjusting for differences in male and female body weights) [66]. In the relationship between leptin and fat mass, it is different from gender. On the one hand, it is because of the inhibitory effect of androgen in blood on leptin. On the other hand, the difference in the amount of leptin in different fat distributions may also play a role. In fact, subcutaneous fat expresses more leptin mRNA than visceral fat [67], while male subcutaneous fat is less than female, so adipose tissue in males may produce less leptin than female adipose tissue. This can explain the difference in fat content in different genders, but it cannot explain that women before and after menopause have different fat distributions but have similar leptin levels. Kastin et al. studied the transfer of peptides from the blood into the brain in mice after ovariectomy and found that the transport of leptin into the brain was lower than that before ovariectomy [68]. Thus, they suggested that the weight gain caused by the loss of ovarian function in mice might be related to the decrease in leptin

Growth hormone (GH) levels are lower in postmenopausal women than that in premenopausal women. Postmenopausal women have changes in body weight and body fat distribution, which may also be caused by changes in growth hormone axis function [69]. Snel et al. found that the fat mass in GH-deficient adults increased, and lean mass decreased [70], and this change could be reversed after supplementation with GH, thus confirming the importance of GH in regulating fat content. GH regulates body weight through the hypothalamic-pituitary axis. Two peptides, growth hormone releasing hormone (GHRH) and growth hormone release inhibiting hormone (GHRIH), secreted by the hypothalamus, activate and inhibit the release of pituitary GH. The stress response of GH to GHRH in postmenopausal women decreases [71]. This response is similar to that in obese and elderly population; MHT supplementation in postmenopausal women can

**104**

Incidence of overweight and obesity is increased in perimenopausal and menopausal women, which is an important public health concern. One of the reasons for increasing obesity during the menopausal transition is the increase in food intake. A combination of biological and psychological factors exerts potent influence on the regulation of appetite and food intake.

### *2.5.1 Estrogen and the central control of appetite*

Women during the menopausal transition had decreased estrogen. Estrogen participates in the regulation of energy homeostasis, as evidenced by an increase in food intake and obesity in ovariectomized rats. In concordance, clinical evidence showed that hunger, desire to eat, and prospective food consumption are all increased during the menopausal transition, while fasting fullness is decreased. This trend persisted in the later postmenopausal years [74]. However, both animal and human studies indicate that overeating due to the lack of estrogen can be ameliorated by estrogen replacement therapy [75].

Control of appetite is mainly performed in the hypothalamus of the central nervous system. Located in this region are arcuate, ventromedial, and paraventricular nuclei. Two major populations of arcuate neurons influence food intake in opposite directions. Neurons that extend projections to the lateral hypothalamic area express neuropeptide Y and Agouti-related peptide, which stimulate food intake and decrease energy expenditure. In other words, they extend orexigenic effects. Other arcuate neurons extend projections to the paraventricular nuclei and express proopiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART), which inhibit food intake and increase energy expenditure. Therefore, they extend anorexigenic effects [76, 77]. Estrogen acts as both a direct and an indirect control of appetite and food intake, modulating both anorexigenic and orexigenic signals in hypothalamus [78]. Estrogen regulates the function of the hypothalamic nuclei through complex processes. While ERα is abundantly expressed in the rodent brain in ventromedial, arcuate, and paraventricular and the medial preoptic area, ERβ expression is significantly lower [79]. Estrogens directly act on POMC neurons and regulate their cellular activity. ERα mRNA level in arcuate POMC neurons fluctuates over the course of the menstrual cycle, with the most dramatic increase on the day of proestrus, when E2 concentration is the highest [77]. In concordance, Xu et al. demonstrated that hypothalamic-specific deletion of ERa in steroidogenic factor-1 (SF1) neurons reduces energy expenditure. Deletion of ERa in POMC neurons alone increases appetite. Simultaneous deletion of ERa in POMC and SF1 neurons can add up these two effects and lead to hypometabolism and hyperphagia [80].

Peptidergic systems known to regulate ingestive behavior include ghrelin, neuropeptide Y (NPY), and melanin-concentrating hormone (MCH). Ghrelin peptide is a hunger-stimulating hormone, which is not only produced in the stomach by parietal cells but also produced in different areas of the hypothalamus, such as the aforementioned arcuate and paraventricular nuclei [81, 82]. Ghrelin regulates food intake by activating the growth hormone receptor according to the fluctuation in carbohydrate and lipid levels. Ghrelin also antagonizes the function of leptin, which promotes a sense of fullness. The antagonizing effect acts through the neuropeptide Y/Y1 receptor pathway, which increases gene expression of NPY and augment food intake [83].

NPY increases food intake potently through the function of the arcuate and paraventricular area in hypothalamus [84]. Estrogen inhibits the orexigenic activity of NPY. This inhibitory action stems from the reduced NPY mRNA expression and receptor activity by estrogen [85].

Melanin-concentrating hormone (MCH) promotes feeding behavior by direct action on the lateral nucleus in hypothalamus [86]. The arcuate and POMC neurons can stimulate the MCH activity [87]. Ovariectomized rats treated with estradiol demonstrated reduced orexigenic effect of MCH [88], which is hypothesized to be a direct effect of the reduced expression of MCH mRNA or the decreased affinity of the MCH receptor [89].

#### *2.5.2 Stress and feeding behavior*

Stress has been tied to a tendency to overeat and a preference for high-fat and high-sugar foods. Animal studies showed that chronic stress stimulates food intake and inhibits hypothalamic-pituitary-adrenal axis activity induced by acute stress [90]. In humans, food craving after stress can be predicted by high cortisol reactivity in response to stress. Epel et al. found that premenopausal women exposed to a stressful situation had higher cortisol levels and experienced higher calorie consumption, and they also tend to prefer sweets. Negative mood induced by stress also leads to greater food consumption [91]. As women experiencing menopausal transition, they are exposed to a lot of distressing symptoms, such as hot flashes, negative mood, poor sleep, recurring infections of the urogenital tract, and so on. Stress arises, which may increase their eating behavior.

Further, stress situations can decrease gastric motility. Estrogen has synergistic actions with stress mediators and interacts with neuromodulators [92]. Estrogen also influences gut function by inhibiting smooth muscle contraction. Premenopausal and postmenopausal women demonstrated a decrease in gastric motility under stress, which was similar to the general population. However, the perimenopausal women exhibited lower basal gastric motility but did not reveal a decreased gastric motility in response to stress. This indicated that many gastric changes during menopause are a rapid response to decreased estrogen levels, which happens quickly and can recover with time even without estrogen replacement [93].

Gaining better understanding of the mechanisms of increased appetite during menopausal transition promises to open novel therapeutic solutions for this population. Since the lack of estrogen plays a key role in the disturbances of food intake, MHT is one of the solutions to prevent unfavorable overeating, metabolic disturbances, and obesity.

## **3. Conclusions**

With the aging of world population, the health issue of postmenopausal women has been unprecedented concerned. Obesity is associated with a decline of lifespan. Especially, the increased risk of weight gain, centrally accumulation of body fat, and energy metabolism disorders during the menopausal transition lead to further CVD and rise overall mortality in women. An early intervention of

**107**

**Author details**

and Jing Shu\*

and shujing@hmc.edu.cn

provided the original work is properly cited.

*Ovarian Hormonal Change-Related Energy Metabolism and Obesity in Menopausal Women*

MHT perimenopause is recommended, which may maintain the energy metabolic homeostasis and increase the average life expectancy. Numerous research studies have elucidated that menopause-related obesity is the combined effects of a variety of neuroendocrine and metabolic pathways, and it is well recognized that ovarian hormone plays a key role. Besides, different regimens of MHT may cause delicate difference on energy metabolism. More studies are necessary to characterize the complex effects of ovarian hormone on the energy metabolism, in which multiple

This work was supported by grants from the National Natural Science Foundation of China [81701460 (X. C.)]; the Natural Science Foundation of Zhejiang Province [Y17H040052 (J. S)] and [LQ18H040004 (J. Z.)]; the General Research Program for Medicine and Health of Zhejiang Province [2019KY033 (J.S.)] and [2016KYA029 (J. Z.)]; and the Excellent Young Scientist Foundation of

Zhejiang Provincial People's Hospital [ZRY2016A002 (X. C.)].

The authors declare no conflict of interest.

Jing Zhu, Mengxia Ji, Lili Xing, Zhizhi Yu, Xiaoyan Guo, Xiaopan Chen\*

People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China

\*Address all correspondence to: chenxiaopan@hmc.edu.cn

Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*DOI: http://dx.doi.org/10.5772/intechopen.89336*

organs and systems are involved.

**Acknowledgements**

**Conflict of interest**

*Ovarian Hormonal Change-Related Energy Metabolism and Obesity in Menopausal Women DOI: http://dx.doi.org/10.5772/intechopen.89336*

MHT perimenopause is recommended, which may maintain the energy metabolic homeostasis and increase the average life expectancy. Numerous research studies have elucidated that menopause-related obesity is the combined effects of a variety of neuroendocrine and metabolic pathways, and it is well recognized that ovarian hormone plays a key role. Besides, different regimens of MHT may cause delicate difference on energy metabolism. More studies are necessary to characterize the complex effects of ovarian hormone on the energy metabolism, in which multiple organs and systems are involved.
