**7. Summary**

296 Sex Steroids

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

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

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

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

preventing an android fat shift (central fat depot) regardless of the body weight.

increase, and cardiovascular effects remain controversial.

postmenopausal women.

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 hormones involved in regulating adiposity remain to be defined.

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 need additional studies.

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 mass) differently than conventional HT.

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.

Adipose Tissue Metabolism and Effect of

954, 1992.

4, pp. 455-464, 1989.

44, no. 2, pp. 183-190, 1991.

10, no. 6, pp. 424-431, 2002.

vol. 141, no. 2, pp. 649-656, 2000.

508, 1978.

2501-2506, 2007.

vol. 15 Suppl 2, pp. 67-81, 1991.

Postmenopausal Hormone Therapy on Change of Body Composition 299

[19] G. Fruhbeck, S. Becerril, N. Sainz et al., "BAT: a new target for human obesity?," *Trends* 

[20] P. Bjorntorp, "Adipose tissue distribution and function," *International Journal of Obesity*,

[21] L. Sjostrom, U. Smith, M. Krotkiewski, and P. Bjorntorp, "Cellularity in different

[22] C. J. Ley, B. Lees, and J. C. Stevenson, "Sex- and menopause-associated changes in

[23] H. Shimokata, R. Andres, P. J. Coon et al., "Studies in the distribution of body fat. II.

[24] C. G. Lee, M. C. Carr, S. J. Murdoch et al., "Adipokines, inflammation, and visceral

[25] W. B. Kannel, L. A. Cupples, R. Ramaswami et al., "Regional obesity and risk of

[26] M. Krotkiewski, P. Bjorntorp, L. Sjostrom, and U. Smith, "Impact of obesity on

[28] M. A. Espeland, M. L. Stefanick, D. Kritz-Silverstein et al., "Effect of postmenopausal

[29] M. N. Dieudonne, R. Pecquery, M. C. Leneveu, and Y. Giudicelli, "Opposite effects of

[30] D. A. Roncari, and R. L. Van, "Promotion of human adipocyte precursor replication by

[31] S. L. Palin, P. G. McTernan, L. A. Anderson et al., "17Beta-estradiol and anti-estrogen

[32] S. Musatov, W. Chen, D. W. Pfaff et al., "Silencing of estrogen receptor alpha in the

*Endocrinology and Metabolism*, vol. 94, no. 4, pp. 1104-1110, 2009.

*Endocrinology and Metabolism*, vol. 82, no. 5, pp. 1549-1556, 1997.

*Clinical and Experimental*, vol. 52, no. 4, pp. 383-388, 2003.

regions of adipose tissue in young men and women," *Metabolism: Clinical and* 

body-fat distribution," *American Journal of Clinical Nutrition*, vol. 55, no. 5, pp. 950-

Longitudinal effects of change in weight," *International Journal of Obesity*, vol. 13, no.

adiposity across the menopausal transition: a prospective study," *Journal of Clinical* 

cardiovascular disease; the Framingham Study," *Journal of Clinical Epidemiology*, vol.

metabolism in men and women. Importance of regional adipose tissue distribution," *Journal of Clinical Investigation*, vol. 72, no. 3, pp. 1150-1162, 1983. [27] J. Munoz, A. Derstine, and B. A. Gower, "Fat distribution and insulin sensitivity in

postmenopausal women: influence of hormone replacement," *Obesity Research*, vol.

hormone therapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Interventions Study Investigators," *Journal of Clinical* 

androgens and estrogens on adipogenesis in rat preadipocytes: evidence for sex and site-related specificities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor gamma2," *Endocrinology*,

17beta-estradiol in culture," *Journal of Clinical Investigation*, vol. 62, no. 3, pp. 503-

ICI:compound 182,780 regulate expression of lipoprotein lipase and hormonesensitive lipase in isolated subcutaneous abdominal adipocytes," *Metabolism:* 

ventromedial nucleus of hypothalamus leads to metabolic syndrome," *Proceedings of the National Academy of Sciences of the United States of America*, vol. 104, no. 7, pp.

*in Pharmacological Sciences*, vol. 30, no. 8, pp. 387-396, 2009.

*Experimental*, vol. 21, no. 12, pp. 1143-1153, 1972.

#### **8. References**


[1] H. N. Polotsky, and A. J. Polotsky, "Metabolic implications of menopause," *Semin Reprod* 

[2] "Obesity: preventing and managing the global epidemic. Report of a WHO consultation," *World Health Organization Technical Report Series*, vol. 894, pp. i-xii, 1-253, 2000. [3] C. L. Ogden, M. D. Carroll, L. R. Curtin et al., "Prevalence of overweight and obesity in the United States, 1999-2004," *JAMA*, vol. 295, no. 13, pp. 1549-1555, 2006. [4] J. C. Lovejoy, C. M. Champagne, L. de Jonge et al., "Increased visceral fat and decreased

[5] R. R. Wing, K. A. Matthews, L. H. Kuller et al., "Weight gain at the time of menopause,"

[6] J. F. Owens, C. M. Stoney, and K. A. Matthews, "Menopausal status influences

[7] J. H. Shin, J. Y. Hur, H. S. Seo et al., "The ratio of estrogen receptor alpha to estrogen

[8] M. P. Brincat, Y. M. Baron, and R. Galea, "Estrogens and the skin," *Climacteric*, vol. 8, no.

[9] F. A. Tremollieres, J. M. Pouilles, C. Cauneille, and C. Ribot, "Coronary heart disease risk

[10] K. Fukami, K. Koike, K. Hirota et al., "Perimenopausal changes in serum lipids and

[11] M. E. Piche, S. J. Weisnagel, L. Corneau et al., "Contribution of abdominal visceral

[12] K. A. Matthews, E. Meilahn, L. H. Kuller et al., "Menopause and risk factors for

[13] S. Gesta, Y. H. Tseng, and C. R. Kahn, "Developmental origin of fat: tracking obesity to

[14] C. R. Balistreri, C. Caruso, and G. Candore, "The role of adipose tissue and adipokines

[15] R. Cancello, and K. Clement, "Is obesity an inflammatory illness? Role of low-grade

[16] R. N. Redinger, "Fat storage and the biology of energy expenditure," *Transl Res*, vol.

[17] M. E. Lean, "Brown adipose tissue in humans," *Proceedings of the Nutrition Society*, vol.

[18] K. A. Virtanen, M. E. Lidell, J. Orava et al., "Functional brown adipose tissue in healthy adults," *New England Journal of Medicine*, vol. 360, no. 15, pp. 1518-1525, 2009.

*Archives of Internal Medicine*, vol. 151, no. 1, pp. 97-102, 1991.

stress," *Circulation*, vol. 88, no. 6, pp. 2794-2802, 1993.

women," *Diabetes*, vol. 54, no. 3, pp. 770-777, 2005.

its source," *Cell*, vol. 131, no. 2, pp. 242-256, 2007.

vol. 113, no. 10, pp. 1141-1147, 2006.

154, no. 2, pp. 52-60, 2009.

48, no. 2, pp. 243-256, 1989.

*Steroids*, vol. 72, no. 6-7, pp. 592-599, 2007.

energy expenditure during the menopausal transition," *Int J Obes (Lond)*, vol. 32, no.

ambulatory blood pressure levels and blood pressure changes during mental

receptor beta in adipose tissue is associated with leptin production and obesity,"

factors and menopause: a study in 1684 French women," *Atherosclerosis*, vol. 142, no.

lipoproteins: a 7-year longitudinal study," *Maturitas*, vol. 22, no. 3, pp. 193-197,

obesity and insulin resistance to the cardiovascular risk profile of postmenopausal

coronary heart disease," *New England Journal of Medicine*, vol. 321, no. 10, pp. 641-

in obesity-related inflammatory diseases," *Mediators of Inflammation*, vol. 2010, p.

inflammation and macrophage infiltration in human white adipose tissue," *BJOG*,

**8. References** 

*Med*, vol. 28, no. 5, pp. 426-434.

6, pp. 949-958, 2008.

2, pp. 110-123, 2005.

2, pp. 415-423, 1999.

1995.

646, 1989.

802078.


Adipose Tissue Metabolism and Effect of

pp. 1809-1818, 2001.

6, pp. 479-491, 2002.

285-292, 1997.

vol. 11, no. 4, pp. 466-473, 2004.

4916-4925.

Postmenopausal Hormone Therapy on Change of Body Composition 301

[46] E. Vegeto, C. Bonincontro, G. Pollio et al., "Estrogen prevents the lipopolysaccharide-

[47] C. M. Brown, T. A. Mulcahey, N. C. Filipek, and P. M. Wise, "Production of

[48] M. Karin, and Y. Ben-Neriah, "Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity," *Annual Review of Immunology*, vol. 18, pp. 621-663, 2000. [49] J. Ye, Z. Gao, J. Yin, and Q. He, "Hypoxia is a potential risk factor for chronic

[51] B. Stein, and M. X. Yang, "Repression of the interleukin-6 promoter by estrogen

[52] F. Lago, R. Gomez, J. J. Gomez-Reino et al., "Adipokines as novel modulators of lipid metabolism," *Trends in Biochemical Sciences*, vol. 34, no. 10, pp. 500-510, 2009. [53] C. Di Carlo, G. A. Tommaselli, and C. Nappi, "Effects of sex steroid hormones and

[54] Y. Zhang, R. Proenca, M. Maffei et al., "Positional cloning of the mouse obese gene and

[55] M. Maffei, J. Halaas, E. Ravussin et al., "Leptin levels in human and rodent:

[56] C. Di Carlo, G. A. Tommaselli, A. Sammartino et al., "Serum leptin levels and body

[57] P. J. Havel, S. Kasim-Karakas, G. R. Dubuc et al., "Gender differences in plasma leptin

[58] M. Rosenbaum, M. Nicolson, J. Hirsch et al., "Effects of gender, body composition, and

[59] H. Shimizu, Y. Shimomura, Y. Nakanishi et al., "Estrogen increases in vivo leptin

[60] K. Kotani, K. Tokunaga, S. Fujioka et al., "Sexual dimorphism of age-related changes in

[61] R. Leenen, K. van der Kooy, P. Deurenberg et al., "Visceral fat accumulation in obese

concentrations," *Nature Medicine*, vol. 2, no. 9, pp. 949-950, 1996.

its human homologue," *Nature*, vol. 372, no. 6505, pp. 425-432, 1994.

*Cellular Biology*, vol. 25, no. 8, pp. 2957-2968, 2005.

*Nature Medicine*, vol. 1, no. 11, pp. 1155-1161, 1995.

*Metabolism*, vol. 81, no. 9, pp. 3424-3427, 1996.

*Metabolic Disorders*, vol. 18, no. 4, pp. 207-202, 1994.

*Journal of Physiology*, vol. 263, no. 5 Pt 1, pp. E913-919, 1992.

*Biology*, vol. 15, no. 9, pp. 4971-4979, 1995.

induced inflammatory response in microglia," *Journal of Neuroscience*, vol. 21, no. 6,

proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta," *Endocrinology*, vol. 151, no. 10, pp.

inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice," *Am J Physiol Endocrinol Metab*, vol. 293, no. 4, pp. E1118-1128, 2007. [50] S. Ghisletti, C. Meda, A. Maggi, and E. Vegeto, "17beta-estradiol inhibits inflammatory

gene expression by controlling NF-kappaB intracellular localization," *Molecular and* 

receptor is mediated by NF-kappa B and C/EBP beta," *Molecular and Cellular* 

menopause on serum leptin concentrations," *Gynecological Endocrinology*, vol. 16, no.

measurement of plasma leptin and ob RNA in obese and weight-reduced subjects,"

composition in postmenopausal women: effects of hormone therapy," *Menopause*,

menopause on plasma concentrations of leptin," *Journal of Clinical Endocrinology and* 

production in rats and human subjects," *Journal of Endocrinology*, vol. 154, no. 2, pp.

whole-body fat distribution in the obese," *International Journal of Obesity and Related* 

subjects: relation to energy expenditure and response to weight loss," *American* 



[33] I. Merchenthaler, M. V. Lane, S. Numan, and T. L. Dellovade, "Distribution of estrogen

[34] D. L. Voisin, S. X. Simonian, and A. E. Herbison, "Identification of estrogen receptor-

[35] L. M. Brown, and D. J. Clegg, "Central effects of estradiol in the regulation of food

[36] P. A. Heine, J. A. Taylor, G. A. Iwamoto et al., "Increased adipose tissue in male and

[38] G. G. Kuiper, E. Enmark, M. Pelto-Huikko et al., "Cloning of a novel receptor

[39] A. Naaz, M. Zakroczymski, P. Heine et al., "Effect of ovariectomy on adipose tissue of

[40] C. E. Juge-Aubry, E. Henrichot, and C. A. Meier, "Adipose tissue: a regulator of

[41] J. Ye, and J. N. Keller, "Regulation of energy metabolism by inflammation: a feedback

[42] I. Harman-Boehm, M. Bluher, H. Redel et al., "Macrophage infiltration into omental

[43] G. Winkler, S. Kiss, L. Keszthelyi et al., "Expression of tumor necrosis factor (TNF)-

[44] G. He, S. B. Pedersen, J. M. Bruun et al., "Differences in plasminogen activator inhibitor

[45] E. Vegeto, S. Belcredito, S. Etteri et al., "Estrogen receptor-alpha mediates the brain

*Sciences of the United States of America*, vol. 100, no. 16, pp. 9614-9619, 2003.

*Federation of Endocrine Societies*, vol. 149, no. 2, pp. 129-135, 2003.

*Hormone and Metabolic Research*, vol. 35, no. 3, pp. 178-182, 2003.

*of the United States of America*, vol. 93, no. 12, pp. 5925-5930, 1996.

*Neurology*, vol. 473, no. 2, pp. 270-291, 2004.

no. 1, pp. 215-228, 1997.

pp. 49-53, 1996.

pp. 758-763, 2002.

2005.

368.

*Biology*, vol. 122, no. 1-3, pp. 65-73.

vol. 92, no. 6, pp. 2240-2247, 2007.

receptor alpha and beta in the mouse central nervous system: in vivo autoradiographic and immunocytochemical analyses," *Journal of Comparative* 

containing neurons projecting to the rat supraoptic nucleus," *Neuroscience*, vol. 78,

intake, body weight, and adiposity," *Journal of Steroid Biochemistry and Molecular* 

female estrogen receptor-alpha knockout mice," *Proceedings of the National Academy of Sciences of the United States of America*, vol. 97, no. 23, pp. 12729-12734, 2000. [37] S. Mosselman, J. Polman, and R. Dijkema, "ER beta: identification and

characterization of a novel human estrogen receptor," *FEBS Letters*, vol. 392, no. 1,

expressed in rat prostate and ovary," *Proceedings of the National Academy of Sciences* 

mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta)," *Hormone and Metabolic Research*, vol. 34, no. 11-12,

inflammation," *Best Pract Res Clin Endocrinol Metab*, vol. 19, no. 4, pp. 547-566,

response in obesity and calorie restriction," *Aging (Albany NY)*, vol. 2, no. 6, pp. 361-

versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity," *Journal of Clinical Endocrinology and Metabolism*,

alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level," *European Journal of Endocrinology / European* 

1 in subcutaneous versus omental adipose tissue in non-obese and obese subjects,"

antiinflammatory activity of estradiol," *Proceedings of the National Academy of* 


Adipose Tissue Metabolism and Effect of

no. 2, pp. 99-104, 2007.

no. 2, pp. 164-173, 2007.

vol. 18, no. 8, pp. 1747-1752, 2003.

no. 1, pp. 7-18, 2007.

*Endocrinology*, vol. 22, no. 7, pp. 381-387, 2006.

tolerability," *BJOG*, vol. 114, no. 12, pp. 1522-1529, 2007.

women," *Endocrinology*, vol. 142, no. 11, pp. 4813-4817, 2001.

*Histochemistry and Cell Biology*, vol. 124, no. 2, pp. 161-165, 2005.

2005.

2002.

708, 2008.

746-755, 2006.

Postmenopausal Hormone Therapy on Change of Body Composition 303

[77] Z. Chen, T. Bassford, S. B. Green et al., "Postmenopausal hormone therapy and body

[78] J. E. Rossouw, G. L. Anderson, R. L. Prentice et al., "Risks and benefits of estrogen plus

[79] H. Yuksel, A. R. Odabasi, S. Demircan et al., "Effects of postmenopausal hormone

[80] H. Yuksel, A. R. Odabasi, S. Demircan et al., "Effects of oral continuous 17beta-

[81] S. R. Cummings, B. Ettinger, P. D. Delmas et al., "The effects of tibolone in older

[82] E. A. Nijland, W. C. Weijmar Schultz, and S. R. Davis, "Effects of tibolone and

[83] M. L. Hammar, P. van de Weijer, H. R. Franke et al., "Tibolone and low-dose

[84] M. L. Bots, G. W. Evans, W. Riley et al., "The effect of tibolone and continuous

[85] W. Hanggi, K. Lippuner, P. Jaeger et al., "Differential impact of conventional oral or

[87] A. Arabi, P. Garnero, R. Porcher et al., "Changes in body composition during post-

[88] D. E. Jacobsen, M. M. Samson, S. Kezic, and H. J. Verhaar, "Postmenopausal HRT and

[89] A. Wiik, M. Ekman, G. Morgan et al., "Oestrogen receptor beta is present in both

composition--a substudy of the estrogen plus progestin trial of the Women's Health Initiative," *American Journal of Clinical Nutrition*, vol. 82, no. 3, pp. 651-656,

progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial," *JAMA*, vol. 288, no. 3, pp. 321-333,

replacement therapy on body fat composition," *Gynecological Endocrinology*, vol. 23,

estradiol plus norethisterone acetate replacement therapy on abdominal subcutaneous fat, serum leptin levels and body composition," *Gynecological* 

postmenopausal women," *New England Journal of Medicine*, vol. 359, no. 7, pp. 697-

raloxifene on health-related quality of life and sexual function," *Maturitas*, vol. 58,

continuous combined hormone treatment: vaginal bleeding pattern, efficacy and

combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study," *European Heart Journal*, vol. 27, no. 6, pp.

transdermal hormone replacement therapy or tibolone on body composition in postmenopausal women," *Clinical Endocrinology*, vol. 48, no. 6, pp. 691-699, 1998. [86] I. B. Meeuwsen, M. M. Samson, S. A. Duursma, and H. J. Verhaar, "The effect of

tibolone on fat mass, fat-free mass, and total body water in postmenopausal

menopausal hormone therapy: a 2 year prospective study," *Human Reproduction*,

tibolone in relation to muscle strength and body composition," *Maturitas*, vol. 58,

muscle fibres and endothelial cells within human skeletal muscle tissue,"



[62] T. Murakami, M. Iida, and K. Shima, "Dexamethasone regulates obese expression in

[63] F. Machinal, M. N. Dieudonne, M. C. Leneveu et al., "In vivo and in vitro ob gene

[64] K. W. Yi, J. H. Shin, H. S. Seo et al., "Role of estrogen receptor-alpha and -beta in

[65] E. Hu, P. Liang, and B. M. Spiegelman, "AdipoQ is a novel adipose-specific gene

[66] P. E. Scherer, S. Williams, M. Fogliano et al., "A novel serum protein similar to C1q,

[67] K. Hotta, T. Funahashi, Y. Arita et al., "Plasma concentrations of a novel, adipose-

[68] Y. Arita, S. Kihara, N. Ouchi et al., "Paradoxical decrease of an adipose-specific protein,

[69] H. Nishizawa, I. Shimomura, K. Kishida et al., "Androgens decrease plasma

[70] S. Horenburg, P. Fischer-Posovszky, K. M. Debatin, and M. Wabitsch, "Influence of sex

[71] C. M. Steppan, S. T. Bailey, S. Bhat et al., "The hormone resistin links obesity to

[72] P. D. Anderson, N. N. Mehta, M. L. Wolfe et al., "Innate immunity modulates

[73] S. S. Pang, and Y. Y. Le, "Role of resistin in inflammation and inflammation-related

[74] M. Bokarewa, I. Nagaev, L. Dahlberg et al., "Resistin, an adipokine with potent

[75] Y. H. Chen, M. J. Lee, H. H. Chang et al., "17 beta-estradiol stimulates resistin gene

[76] R. J. Norman, I. H. Flight, and M. C. Rees, "Oestrogen and progestogen hormone

*and Vascular Biology*, vol. 20, no. 6, pp. 1595-1599, 2000.

diabetes," *Nature*, vol. 409, no. 6818, pp. 307-312, 2001.

diseases," *Cell Mol Immunol*, vol. 3, no. 1, pp. 29-34, 2006.

214, no. 3, pp. 1260-1267, 1995.

no. 11, pp. 2393-2399, 2008.

pp. 26746-26749, 1995.

257, no. 1, pp. 79-83, 1999.

*Research*, vol. 40, no. 11, pp. 779-786, 2008.

9, pp. 2734-2741, 2002.

6, pp. 2272-2279, 2007.

147, no. 9, pp. 4496-4504, 2006.

2005.

1999.

10703, 1996.

isolated rat adipocytes," *Biochemical and Biophysical Research Communications*, vol.

expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroid hormones," *Endocrinology*, vol. 140, no. 4, pp. 1567-1574,

regulating leptin expression in 3T3-L1 adipocytes," *Obesity (Silver Spring)*, vol. 16,

dysregulated in obesity," *Journal of Biological Chemistry*, vol. 271, no. 18, pp. 10697-

produced exclusively in adipocytes," *Journal of Biological Chemistry*, vol. 270, no. 45,

specific protein, adiponectin, in type 2 diabetic patients," *Arteriosclerosis, Thrombosis,* 

adiponectin, in obesity," *Biochemical and Biophysical Research Communications*, vol.

adiponectin, an insulin-sensitizing adipocyte-derived protein," *Diabetes*, vol. 51, no.

hormones on adiponectin expression in human adipocytes," *Hormone and Metabolic* 

adipokines in humans," *Journal of Clinical Endocrinology and Metabolism*, vol. 92, no.

proinflammatory properties," *Journal of Immunology*, vol. 174, no. 9, pp. 5789-5795,

expression in 3T3-L1 adipocytes via the estrogen receptor, extracellularly regulated kinase, and CCAAT/enhancer binding protein-alpha pathways," *Endocrinology*, vol.

replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution," *Cochrane Database Syst Rev*, no. 2, p. CD001018, 2000.


**15** 

Toshihide Kubo

*Japan* 

**Standard Gonadotropin-Suppressive Therapy** 

Estrogen deprivation, for instance after ovariectomy or natural menopause, is associated with significant bone loss in adult women. (Lindsay, 1995) Gonadotropin-releasing hormone agonist (GnRHa) inhibits hypothalamo-pituitary-gonadal hormone secretion and gradually reduces the estrogen level. (Wacharawsindhu et al., 2006) Consequently, decreases in bone mineral density, which are also observed after ovariectomy and natural menopause, have been observed during GnRHa therapy in women with endometriosis and men with benign prostatic hyperplasia. (Goldray et al., 1993) Moreover, women who were treated with this analog showed body composition changes, including a decrease in lean mass and an increase in fat mass, which resemble the body changes that occur during the

Meanwhile, GnRHa has also been the treatment of choice for central precocious puberty (CPP) since the mid-1980s. (Crowley et al., 1981) Many of the previous studies on the auxological effects of GnRHa treatment on CPP have focused on assessing the patient's final height, whereas much less attention has been paid to changes in their weight and body

However, concern has been expressed that CPP might be associated with increases in body mass index (BMI) both at the initial presentation and during GnRHa treatment (Boot et al., 1998) and that individuals with the condition are prone to developing obesity. This concern

On the other hand, it is well known that BMI and percentage body fat increase during puberty. Consequently, gonadotropin-suppressive therapy can theoretically halt the

Recently, there have been many reports about the changes in body composition that occur in children with CPP who are treated with GnRHa (Wacharsindhu et al., 2006, Arrigo et al., 2004, Boot et al., 1998, Feuillan et al.,1999, Palmert et al., 1999, Chiumello et al., 2000, van der Sluis et al., 2002, Paterson et al., 2004, Oosdijk et al., 1996, Traggiai et al., 2005, Herger et al., 1999, Pasuquino et al., 2008). Some reports have shown that obesity occurs at a high frequency among children with CPP (Arrigo et al., 2004, Feuillan et al., 1999, Palmert et al.,

is supported by adult cases that were treated with GnRHa, as described above.

progression to obesity by inhibiting pubertal development.

**1. Introduction** 

menopause. (Revila et al., 1998)

composition. (Arrigo et al., 2004)

**in Japanese Girls with Idiopathic Central** 

**Precocious or Early Puberty Does Not** 

**Adversely Affect Body Composition** 

*National Hospital Organization, Okayama Medical Center* 


