**2.1 The influence of menopause on adipose distribution and menopausal hormone therapy**

### *2.1.1 Adipose distribution at menopause*

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

In this chapter, we summarize the evidence from clinical and animal studies and target to explain how hormonal changes in menopause lead to alterations in lipid

*Schematic illustration of possible pathophysiology underlying the ovarian hormone changes related to energy* 

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**Figure 2.**

**Figure 1.**

*Graphical overview on the contents of this chapter.*

*metabolism and obesity in menopause women.*

The body adipose tissue distribution is different between males and females. The figure of men is pear shaped, since the adipose tissue tends to accumulate on the subcutaneous and intra-abdominal part. Whereas women's figure is apple shaped, since women's fat is more likely to accumulate on gluteal and femoral part [5]. However, mounting evidence indicated that postmenopausal women underwent deleterious changes of body adipose tissue distribution, from noncentral adiposity to central adiposity, which leads to an increased risk of CVD [6–8].

A number of factors contribute to the altered body adipose tissue distribution in postmenopausal women, including age, menopause, appetite, physical activity, and emotional changes, while age and menopause are the main reasons. A prospective study carried by Ho et al. concerning Chinese women aged 44–55 showed that the body fat percentage and central adiposity were higher among perimenopausal and postmenopausal women than that in premenopausal women [6]. Another study followed up by Caucasus and black women for 4 years and found that menopause was related to total fat increase and visceral fat increase [7]. A meta-analysis revealed that the decrease in total leg fat percentage and increase in measures of central fat were related to menopause, while increasing age was a predominant contributor [8]. This epidemiological and clinical evidence suggests that ovarian hormone may play a major role in the regulation of adipose tissue distribution.

Since 1990s, accumulating evidence suggests that androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) are present in adipose tissues [5]. Ovarian hormones enter the cell and bind to their specific receptors, and then the complex regulates the transcription of targeted genes. Lipoprotein lipase (LPL) is one of the most important proteins that are involved in lipid deposition. LPL is the key enzyme hydrolyzing the circulating triglycerides into glycerol and free fatty acids, which accumulate in the adipose tissues. The hormonal regulation of LPL in adipose tissues is complicated. Generally, growth hormone and estrogen inhibit lipid accumulation by suppressing the activity of LPL, while cortisol and insulin appear to exert opposite function [5].

Iverius et al. found that fasting plasma LPL activity was inversely correlated with plasma estradiol levels and positively correlated with plasma-free testosterone in obese women [9]. One study observed that when 17β-estradiol patch was placed transdermally in the gluteal region of postmenopausal women, LPL in adipose tissue from beneath was significantly decreased compared to placebo group [10]. It is also found that compared to premenopausal women, postmenopausal women have lower LPL activity in femoral adipose tissue, whereas abdominal LPL activity is comparable [11]. Palin et al. found that estrogen regulates LPL activity in a dosedependent manner, the highest concentration of estrogen 10<sup>−</sup><sup>7</sup> mol/L significantly reduced LPL expression relative to control, while the lower concentration significantly increased LPL expression relative to control [12]. However, whether estrogen 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].

## *2.1.2 Menopausal hormone therapy-related body fat distribution*

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

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