**2.2 The influence of menopause on glucose metabolism and menopausal hormone therapy**

### *2.2.1 Glucose metabolism at menopause*

The incidence of glucose intolerance and insulin resistance increases after menopause [22]. The underlying pathogenesis of impaired glucose metabolism, although not yet fully understood, has been linked to estrogen deficiency, which is one of the characteristic changes arising with menopause. Estrogen exerts its protective effects on glycometabolism via various ways:

1.Increase insulin synthesis: Estradiol-stimulated estrogen receptor α (ERα) activates the Src/MAPK pathway, phosphorylates the transcription factor

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PDX-1, and enhances NeuroD1 nuclear localization and its binding to the insulin promoter [23]. As a result, insulin gene transcription is upregulated,

2.Regulate insulin release: On one hand, estrogen inhibits basal insulin secretion, which is mainly mediated by estrogen receptor β (ERβ). After an overnight fast, ERβ knockout mice carry lower blood glucose level than their counterparts in the control group and ERα gene knockout group [24]. On the other hand, estrogen promotes glucose-stimulated insulin secretion, which is mainly mediated by its plasma membrane receptor. This pathway regulates the activity of membrane-bound guanylate cyclase and activates protein kinase G. Subsequently, ATP-sensitive K+ channels close, and calcium channels open, triggering the insulin release [25].

3.Decrease insulin-mediated glucose uptake: Study suggests that the use of estrogen or combined estrogen-progesterone therapy in women may alter glycogen synthesis, GLUT4 translocation, and other early steps in the insulin-signaling

4.Reduce insulin resistance: Low estrogen is found to be an independent predictor of insulin resistance [27]. Elevated cytosolic free calcium may be the basis of insulin resistance. It is believed that estrogen as a calcium channel blocker may reduce cytosolic calcium, antagonizing the process of insulin resistance [28].

5.Protect pancreatic β cells against inflammation-induced apoptosis: Estrogen activates Src/MAPK, PI3K/Akt signaling pathway, upregulates liver receptor homolog −1, promotes glucocorticoid synthesis, suppresses interleukin-1 and interleukin-6 transcription, and thus protects human islets against inflamma-

6.Reduce pro-inflammatory cytokines: Estrogen reduces pro-inflammatory cytokines in adipose tissue. It is noted that the level of TNFα, MCP-1, IL6, and macrophages increases after oophorectomy in mice [30]. By inhibiting inflam-

After menopause, the above protective effects are impaired due to a dramatic reduction in estrogen, leading to a decreased level of insulin synthesis and glucosestimulated secretion. At the same time, however, the inactivation and clearance of insulin are slowed in aging liver and kidney, and the serum insulin concentration

MHT improves the quality of life in postmenopausal women by treating a range of symptoms with exogenous hormone supplement, using estrogen together with other hormones. However, current evidence concerning the effects of MHT on

It was found that a low estrogen status is more detrimental to glycometabolism. The second national health and nutrition survey in the United States revealed that the risk of Type 2 diabetes in postmenopausal women was significantly higher than premenopausal women. Moreover, 40~50% of menopausal women were reported

Further studies confirmed that estrogen has a dual effect on insulin sensitivity: appropriate estrogen improves insulin sensitivity, while high dose estrogen

matory responses, estrogen can improve the insulin sensitivity.

*2.2.2 Menopausal hormone therapy-related glucose metabolism*

pathway, which in turn decreases whole-body glucose uptake [26].

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

and insulin synthesis increased.

tion-induced apoptosis [29].

exhibits an overall upward trend.

glycometabolism remains controversial.

to have reduced insulin sensitivity.

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

PDX-1, and enhances NeuroD1 nuclear localization and its binding to the insulin promoter [23]. As a result, insulin gene transcription is upregulated, and insulin synthesis increased.


After menopause, the above protective effects are impaired due to a dramatic reduction in estrogen, leading to a decreased level of insulin synthesis and glucosestimulated secretion. At the same time, however, the inactivation and clearance of insulin are slowed in aging liver and kidney, and the serum insulin concentration exhibits an overall upward trend.

#### *2.2.2 Menopausal hormone therapy-related glucose metabolism*

MHT improves the quality of life in postmenopausal women by treating a range of symptoms with exogenous hormone supplement, using estrogen together with other hormones. However, current evidence concerning the effects of MHT on glycometabolism remains controversial.

It was found that a low estrogen status is more detrimental to glycometabolism. The second national health and nutrition survey in the United States revealed that the risk of Type 2 diabetes in postmenopausal women was significantly higher than premenopausal women. Moreover, 40~50% of menopausal women were reported to have reduced insulin sensitivity.

Further studies confirmed that estrogen has a dual effect on insulin sensitivity: appropriate estrogen improves insulin sensitivity, while high dose estrogen

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

*2.1.2 Menopausal hormone therapy-related body fat distribution*

activity should also be included in weight management [21].

**2.2 The influence of menopause on glucose metabolism and menopausal** 

The incidence of glucose intolerance and insulin resistance increases after menopause [22]. The underlying pathogenesis of impaired glucose metabolism, although not yet fully understood, has been linked to estrogen deficiency, which is one of the characteristic changes arising with menopause. Estrogen exerts its protective effects

1.Increase insulin synthesis: Estradiol-stimulated estrogen receptor α (ERα) activates the Src/MAPK pathway, phosphorylates the transcription factor

the unfavorable body fat redistribution and reduce the overall fat mass.

regulates LPL activity directly or indirectly remains unclear. A research from the rat model suggested that ovarian hormones exerted their regulation of LPL activity indirectly through their effect on growth hormone [13]. However, Homma and his colleagues found that estrogen markedly decreased the LPL mRNA using genetically manipulated cells and demonstrated a special sequence that was responsible for suppressing the LPL gene transcription by estrogen [14]. There might be a nongenomic mechanism existing for the regulation of ovarian hormone, which responses more rapidly, since ER was found in cellular membranes of subcutaneous abdominal and omental human adipose tissues. But the mechanism has not been completely elucidated. It appears that various components of the membrane signaling systems were involved, including the cAMP cascade and the phosphoinositide cascade [5].

Since the increases in total body fat and abdominal fat are associated with hormonal changes during menopause transition period, MHT may help to ameliorate

Our team found that in ovariectomized mice, the estrogen-treated group gained less weight and had significantly lower visceral adipose mass and smaller adipocyte size than nontreated group [15]. A randomized study found that hip and abdominal circumferences and fat mass/fat-free mass ratio over the abdomen in women who received only estrogen therapy were significantly declined [16]. Postmenopausal women who used continuous combined regimen of 17-β estradiol plus norethisterone acetate showed significantly reduced central fat accumulation as assessed by waist circumference and subcutaneous abdominal fat thickness after a 6-month follow-up [17]. One study concerning the randomized controlled clinical trial of the Women's Health Initiative (WHI) showed that after 3 years of intervention with estrogen plus progestin, the treated group of women lost less lean soft tissue mass than the placebo group. Additionally, the women in the treated group had less upper-body fat distribution than the women in the placebo group [18]. Other studies compared different routes of estrogen replacement therapy and discovered that oral estrogen treatment resulted in an increase in fat mass of 5% and a decrease in lean body mass of 2%, which is equivalent to those occurring spontaneously over a 5–10-year period, whereas the transdermal estrogen did not bring a significant change in fat mass and lean mass [19, 20]. Though the conclusion is controversial, the International Menopause Society (IMS) puts it in their recommendation that menopausal abdominal fat accumulation can be ameliorated by estrogen therapy, with a reduction in overall fat mass, and maintain that a healthy diet and physical

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**hormone therapy**

*2.2.1 Glucose metabolism at menopause*

on glycometabolism via various ways:

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

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

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 glucose level [35].

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 glycometabolism [36].

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

#### *2.3.1 Lipid metabolism at menopause*

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 HDL-C [43].

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 atherosclerosis in women [50].

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

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lipid profile.

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

ovariectomized mice, indicating that AQP7 might be a novel checkpoint involved in the regulatory network of estrogen during menopausal obesity [15, 51]. Following up these studies, the molecular details that link AQP7 to estrogen were examined by analyzing the physical interactions between the promoter site of AQP7 and ER in our latest publication [52]. From there, we provided the first evidence that ER directly bound the estrogen response elements (EREs) in the promoter area of the Aqp7 gene and transcriptionally controlled AQP7 expression upon estrogen exposure. Therefore, there is solid ground for suggesting that Aqp7 is a direct target gene of ERs and may serve as a potential molecular target for the prevention of

In a recent study performed by Song et al., research focuses on the effects of FSH on lipid metabolism and has suggested that the marked increase of FSH expression postmenopausal combined with its receptors in liver may also reduce LDL-receptor level and subsequently result in a weakness of LDL-C endocytosis and an elevation

Taken together, the above observations emphasize the gender differences and age independent on the lipid changes around the final menstrual period and suggest that ovarian hormone may influence the hepatic lipid synthesis, reduce the lipid circulation, upregulate the lipolysis, and lead to protective cardiometabolic effects. Growing body of literatures indicated several related functional proteins might play a crucial role in sex hormone's regulation of lipid metabolism; however, presented findings of the studies as well as the conclusion need further verification, but they are promising. Therefore, the complex association of menopause, ovarian hormone, especially estrogen, and lipid metabolism needs further extensive experimentation.

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

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 metabo-

lism, exerting favorable and unfavorable changes. The choice for a particular regimen should consider individual demands, indications, complications, and

*2.3.2 Menopausal hormone therapy-related lipid metabolism*

transition has not been mentioned [21].

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

menopausal obesity.

of circulating LDL-C level [53].

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

ovariectomized mice, indicating that AQP7 might be a novel checkpoint involved in the regulatory network of estrogen during menopausal obesity [15, 51]. Following up these studies, the molecular details that link AQP7 to estrogen were examined by analyzing the physical interactions between the promoter site of AQP7 and ER in our latest publication [52]. From there, we provided the first evidence that ER directly bound the estrogen response elements (EREs) in the promoter area of the Aqp7 gene and transcriptionally controlled AQP7 expression upon estrogen exposure. Therefore, there is solid ground for suggesting that Aqp7 is a direct target gene of ERs and may serve as a potential molecular target for the prevention of menopausal obesity.

In a recent study performed by Song et al., research focuses on the effects of FSH on lipid metabolism and has suggested that the marked increase of FSH expression postmenopausal combined with its receptors in liver may also reduce LDL-receptor level and subsequently result in a weakness of LDL-C endocytosis and an elevation of circulating LDL-C level [53].

Taken together, the above observations emphasize the gender differences and age independent on the lipid changes around the final menstrual period and suggest that ovarian hormone may influence the hepatic lipid synthesis, reduce the lipid circulation, upregulate the lipolysis, and lead to protective cardiometabolic effects. Growing body of literatures indicated several related functional proteins might play a crucial role in sex hormone's regulation of lipid metabolism; however, presented findings of the studies as well as the conclusion need further verification, but they are promising. Therefore, the complex association of menopause, ovarian hormone, especially estrogen, and lipid metabolism needs further extensive experimentation.
