**6. Postmenopausal hormone therapy and change in body composition**

Hormone therapy (HT) is widely used for the treatment of menopausal symptoms and preventing bone loss in postmenopausal women. Estrogen replacement, when combined with various progestogens for endometrial protection, has been established as a conventional formulation. The benefit of HT is known to reduce vasomotor symptoms,

Adipose Tissue Metabolism and Effect of

need for a long-term observational study.

1, independent of the serum IGF-1 level [92].

hormones involved in regulating adiposity remain to be defined.

decreased.

**7. Summary** 

need additional studies.

mass) differently than conventional HT.

Postmenopausal Hormone Therapy on Change of Body Composition 297

effects with traditional estrogen therapy (ET)/HT on relieving vasomotor symptoms/ genital atrophy, improving the quality of life, and preventing bone loss in postmenopausal women [81-84]. Currently 4 studies have shown the effects of tibolone on BW or body composition in postmenopausal women. In a 2-year follow up study comparing three regimens of HRT, tibolone had a stable effect on body fat and lean mass [85]. However, the fat mass increased (+3.6%) and the lean body mass decreased (-1.7%) in the control group. Another study demonstrated that tibolone significantly increased fat-free mass by 0.85 kg and total body water by 0.78 liter during a 1-year observation period [86]. The authors reported an effect of tibolone on preventing a decline in lean body mass, but mentioned the

Arabi et al. compared the effects of tibolone with EPT (E2/NETA) on changes in body composition and bone densitometry in postmenopausal women [87]. Both EPT and tibolone increased lean body mass, whereas the android fat and android obesity index

Tibolone might provide further benefits in increasing lean body mass and decreasing the fat component. Steroid hormones exert their action by binding to an intra-nuclear receptor [88]. Therefore, like estrogen, tibolone might have a direct effect on skeletal muscle by binding to ERα or ERβ expressed within human skeletal muscle [88-90]. In addition, tibolone increases the serum IGF-1 levels [91], which promotes muscle protein synthesis, and increases the number of myogenic satellite cells and the proliferation of myogenic satellite cells. The anabolic effect of tibolone on muscle has been suggested to be mediated in part by local IGF-

Adipose tissue is the largest endocrine organ in the human body. The amount and distribution of adipose tissue reflects energy balance. Adipose tissue also releases a variety of biologically active molecules or cytokines. Adipocyte metabolism and physiology have been extensively studied over recent years, but the exact mechanism and effect of sex steroid

Current data give evidence that estrogen appears to have direct effects on cell proliferation or differentiation for adipocytes, and in regulating key enzymes involved in fat deposition. Another possible mechanism involves the hormonal or paracrine effects by secretion of various adipokines and cytokines, in which interactions with estrogen are promising and

At present, it is not known whether or not HT provides a significant effect on modulating fat mass or preventing fat redistribution. Furthermore, in recent years the HT formulations have been changed to include lower doses of estrogen (< 50 μg) in combination with new progestins. The effects of the currently used HT regimens on changes in body fat composition are limited and require more data. Tibolone includes estrogenic, androgenic, and progestogenic properties which may affect the body composition (adipose tissue or lean

The respective roles of sex steroid hormones and their receptors (ER subtypes and PR) on body fat distribution could be an interesting target for understanding the estrogen effect on adiposity, and may provide selective therapeutic approaches, such as hormonal manipulation for adiposity related to estrogen change throughout the menopausal period.

prevent osteoporotic fractures, and improve well-being and quality of life during the menopausal period. In contrast, the risks for breast cancer and thromboembolic disease may increase, and cardiovascular effects remain controversial.

As previously mentioned, aging and menopause in women are related to an increase in body fat and redistribution of fat mass to the central portion of the body. These changes are linked to an increase in metabolic and cardiovascular disease after the menopause. Therefore, it has been continuously questioned and theorized that HT may have a favorable effect on change in body composition and anthropometries in postmenopausal women. With respect to this issue, data are still debated. In a meta-analysis of 24 RCTs, no effect of ET or HT on body weight was described [76]. However, subsequent studies suggested some beneficial effects of HT on body composition. A sub-study of the estrogen plus progestin trial of the Women's Health Initiative (WHI) investigated whether or not postmenopausal HT affects age-related changes in body composition [77]. The WHI study was originally designed to evaluate the risks and benefits of HT (EPT/ET) with an enrollment of 16,608 postmenopausal women between 1993 and 1998 [78]. The sub-analysis included 835 women who had whole-body dual-energy X-ray absorptiometry scans for measurement of body composition at baseline and year 3. Based on the results of the study, women who received EPT lost less lean soft tissue mass (-0.04 kg) than women who received placebo (-0.44 kg) 3 year after intervention. Furthermore, less upper-body fat distribution was noted in the EPT group than the placebo group (ratio of trunk to leg fat mass, -0.025 for the EPT group and 0.004 for the placebo group, *P* = 0.003). The investigators concluded that EPT has a favorable effect by reducing central fat deposition, but the real health benefits of this effect remains to be confirmed due to the small size of the effect. In a randomized, singleblind study, the effects of HT on body fat composition were studied in 59 postmenopausal women (mean age 49.9 ± 3.8 years) [79]. The participants were assigned into the following three groups according to the type of HT: transdermal estradiol (E2)/norethisterone acetate (NETA); transdermal continuous E2/ oral medroxyprogesterone acetate (MPA); and oral continuous E2/NETA. The results showed that all types of HT caused a significant decrease in WC, subcutaneous fat, and WHR. Thus, HT reduced fat deposition in the central part of the body, and such an effect was more marked in women with a WC ≥ 88 cm and subcutaneous fat ≥ 33 cm. Another placebo-controlled study investigated the effects of oral continuous E2/NETA on anthropometric changes and serum leptin levels in postmenopausal women [80]. In agreement with a previous study, WC and HC decreased significantly in the E2/NETA group, while the body weight (BW) increased in the placebo group. With this reduction in central fat deposition, the serum leptin levels were positively related to the changes in subcutaneous fat tissue. The authors advocated that HT may have a protective effect on CVD via a slimming effect on the central region in postmenopausal women.

Although the effect of postmenopausal HT on the change of body composition is not clearly understood, the limited data have suggest that HT has a small, but significant effect on preventing an android fat shift (central fat depot) regardless of the body weight.

Tibolone is a synthetic steroid hormone that exerts estrogenic, androgenic, and progestogenic properties. The biological actions of tibolone are mediated through the metabolites of tibolone (3α-OH-tibolone, 3β-OH-tibolone, and Δ4-isomer) by binding estrogen or progesterone receptors in multiple target tissues and organs (brain, bone, breast, and endometrium). Based on several randomized trials, tibolone has shown comparable effects with traditional estrogen therapy (ET)/HT on relieving vasomotor symptoms/ genital atrophy, improving the quality of life, and preventing bone loss in postmenopausal women [81-84]. Currently 4 studies have shown the effects of tibolone on BW or body composition in postmenopausal women. In a 2-year follow up study comparing three regimens of HRT, tibolone had a stable effect on body fat and lean mass [85]. However, the fat mass increased (+3.6%) and the lean body mass decreased (-1.7%) in the control group. Another study demonstrated that tibolone significantly increased fat-free mass by 0.85 kg and total body water by 0.78 liter during a 1-year observation period [86]. The authors reported an effect of tibolone on preventing a decline in lean body mass, but mentioned the need for a long-term observational study.

Arabi et al. compared the effects of tibolone with EPT (E2/NETA) on changes in body composition and bone densitometry in postmenopausal women [87]. Both EPT and tibolone increased lean body mass, whereas the android fat and android obesity index decreased.

Tibolone might provide further benefits in increasing lean body mass and decreasing the fat component. Steroid hormones exert their action by binding to an intra-nuclear receptor [88]. Therefore, like estrogen, tibolone might have a direct effect on skeletal muscle by binding to ERα or ERβ expressed within human skeletal muscle [88-90]. In addition, tibolone increases the serum IGF-1 levels [91], which promotes muscle protein synthesis, and increases the number of myogenic satellite cells and the proliferation of myogenic satellite cells. The anabolic effect of tibolone on muscle has been suggested to be mediated in part by local IGF-1, independent of the serum IGF-1 level [92].
