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Role of Postmenopausal Hormone Replacement Therapy on Body Fat Gain and Leptin Levels

Posted on: Sunday, 3 July 2005, 03:00 CDT

Abstract

During menopause women tend to gain body fat. The increase in adiposity seems to be a consequence of the decline in endogenous estrogens and the reduced energy expenditure. The role of post- menopausal hormone replacement therapy (pHT) in modulating visceral obesity is controversial. Some studies have shown that pHT has no effect on body weight while in other studies pHT increased body weight. Leptin is an adipocyte-derived hormone and its levels reflect the amount of adipose tissue. Obesity is associated with elevated serum leptin levels. The effect of pHT on leptin levels is also controversial. In some studies pHT increased leptin levels while other studies have not confirmed this increasing effect. The major problem encountered during administration of hormone therapy seems to be the timing of pHT initiation which is a strong confounder on the effect of pHT on leptin levels in postmenopausal women.

Keywords: Estrogen, hormone therapy, leptin, adiposity, postmenopausal

Introduction

Most women in developed countries will live a third of their lives after menopause. Age at menopause varies between individuals, with a mean of about 50 years [1]. Menopause is marked by a rise in levels of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and a fall in the level of estrogen [2]. Estrogen deficiency is associated with climacteric symptoms of urogenital atrophy and bone loss (osteoporosis). Furthermore, during menopause women tend to gain body fat, and this increase in adiposity seems to be a consequence of the decline in endogenous estrogens and the reduced energy expenditure that occurs at this time [2].

Obesity is a chronic disease that is increasing in prevalence, and is characterized by excessive accumulation of body fat. Obesity is denned as body mass index (BMI) > 30 kg/m^sup 2^, with BMI being the weight in kilograms divided by the square of height in meters. Obesity poses a serious risk for the development of diabetes mellitus, hypertension, heart disease, gallbladder disease and certain forms of cancer [3,4].

Leptin is the product of the ob (lep) gene, which is located on chromosome 6 in the mouse and on chromosome 7q31.3 in man [5]. This gene is estrogen-dependent. Leptin is produced by adipose cells, with its levels reflecting the amount of adipose tissue. In the hypothalamus, leptin acts on the arcuate ventromedial and lateral regions, which express high levels of leptin receptor [6]. Hormone replacement therapy (HRT) administered during menopause might prevent or reduce body fat gain. However, existing clinical data addressing this issue are discordant [7]. Several authors have investigated plasma leptin levels in postmenopausal women who are either users or non-users of HRT. Most of the studies reported no differences in serum leptin levels between pre- and postmenopausal women, while others showed both decreased and increased leptin levels.

In the present review, we examine the relationship of HRT to obesity developing during the menopause.

Menopause and hormone replacement therapy

Administration of estrogen or estrogen plus progestogen alleviates postmenopausal symptoms, and HRT is commonly prescribed for their prevention [8]. Although HRT is no longer primarily indicated for the prevention of bone loss, which is accelerated during menopause, its administration favors bone remodeling. Typical symptoms that arise during this period of life are of vasomotor origin such as hot flushes and night sweats, sleep disorders and mood swings. Furthermore, urogenital atrophy and resultant dyspareunia will often affect women's libido. The frequency, severity and duration of symptoms vary widely between individuals and can continue long into the postmenopausal period [1].

Table I. Hormone replacement therapy (HRT) for postmenopausal women, and alternative therapies and routes of HRT administration.

HRT can be administered orally, transdermally, topically, intranasally and as subcutaneous implants (Table I). Prolonged use of HRT might increase the risk of breast cancer [9] and thromboembolic events, while it prevents bone loss and colorectal cancer. The administration of estrogen therapy to non- hysterectomized women is related to an increased risk for endometrial cancer [10].

Tibolone is a selective tissue estrogenic activity regulator administered to postmenopausal women. Tibolone relieves climacteric complaints and prevents bone loss without stimulating the endometrium and breast. Tibolone is metabolized in the liver and intestine into 3α- and 3β-hydroxy metabolites and the 3- keto-Δ4 metabolite. The 3-hydroxy metabolites activate only the estrogen receptor (ER), whereas the 3-keto-A4 metabolite stimulates both progesterone and androgen receptors, but not the ER. Tibolone does not stimulate the endometrium because it is converted locally into its metabolically stable 3-ketoΔ4 metabolite, which shows progestogenic activity [11].

Raloxifene is a non-steroidal benzothiophene that acts as a selective estrogen receptor modulator. It partially mimics the effects of estrogen on bone and the cardiovascular system while it functions as an anti-estrogen in endometrial and breast tissue. The lack of a stimulatory effect on the endometrium and the reduction in invasive breast cancer incidence suggest that raloxifene may be a good candidate for prolonged anti-osteoporotic treatment during menopause [12]. Long-term effects of raloxifene on serum lipids, blood pressure, glucose metabolism and hemostatic cardiovascular risk factors have not been extensively investigated. Gerdien and colleagues found that when administered to healthy postmenopausal women, raloxifene and conjugated equine estrogens (CEE) have similar beneficial effects on cholesterol, low-density lipoproteins and fibrinogen levels. In contrast to CEE, raloxifene did not affect the levels of highdensity lipoproteins, triglycerides, plasminogen activator inhibitor-1, pro thrombin fragment F1+2 and C-reactive protein [13].

Obesity

Obesity is the excessive accumulation of body fat. The total amount of fat, as well as its body distribution, is important for physiology. Central distribution (android-type obesity) of fat tissue is related to increased health risk. Fat distribution in the femoral region (gynoid-type obesity) has been suggested to be metabolically benign and some investigators have even suggested that it could be a marker of a cardioprotective metabolic profile. The most accurate way to measure central obesity is by magnetic resonance imaging or computer-assisted tomography scanning, but this approach is expensive for routine use. Simple anthropometric measurements can be used such as waist circumference. A waist circumference of > 102 cm in men and > 88 cm in women is a risk factor for insulin resistance, diabetes mellitus and cardiovascular disease. There is a clear genetic predisposition to obesity, which is considered to depend on multiple genes. The genetic contribution to obesity is between 25 and 40% of the individual differences in BMI [14,15].

The role of insulin resistance in metabolic diseases has received considerable attention in recent years [16]. Insulin resistance has been suggested to be an important risk factor in the development of the metabolic syndrome, a cluster of disorders comprising glucose intolerance, dyslipidemia, hypertension and dysfibrinolysis that is associated with type 2 diabetes and cardiovascular disease [17]. Obesity has been incriminated to cause or aggravate insulin resistance. It is evident that obesity is a risk factor for these same conditions and that this association is not only related to the degree of obesity, but also appears to be critically dependent on the type of body fat distribution. Thus, individuals with greater degrees of central adiposity appear to develop this syndrome more frequently than individuals with a peripheral body fat distribution [18,19].

Obesity, leptin and ovarian function

Mutations in four already cloned genes cause obesity in animals. Some of them appear to be important in human biology. One of these genes, the ob (lep) gene is expressed only in adipose tissue. Mutations of the leptin gene cause obesity in animals. In the recessively inherited oblob obesity in mice, both copies of the gene are defective because of the presence of a stop codon that truncates the protein at amino acid 105 [3,4] (Table II).

Table II. Genes involved in animal models of obesity that are important in human biology.

Body adiposity has been shown to be a major determinant of circulating leptin [20]. The levels of both leptin mRNA in fat cells and circulating leptin are increased in animal and human obesity. In both genders the subcutaneous fat depot seems to be a stronger predictor of leptin levels than intra-abdominal fat [21]. Sex steroids seem to influence leptin secretion.

Do sex steroids influence leptin secretion and vice versa? Leptin possesses a sexual dimorphism, being higher in women than in men of equivalent age and BMI even after correction for body fat mass [22]. Leptin pulse amplitude is two to three times higher in women than in men and the expression rate of leptin mRNA in subcutaneous fat tissue is significantly higher in females than in males. Moreover, in vitro, the leptin secret\ion rate from men's subcutaneous adipose tissue is 66% that of women's [23]. Leptin increases with the progression of puberty in girls and varies throughout the menstrual cycle [24]. In some studies, leptin levels are negatively correlated with androgen levels. In vitro studies have explored the direct influence of leptin expression in the subcutaneous adipose tissue of men and women after a short exposure (24 h) to androgens and estrogens.

Are changes in leptin mediated by estrogens? It seems that leptin expression in adipose tissue is stimulated by estrogens and estrogen precursors in women, suggesting that the sexual dimorphism of leptinemia in humans is ER-dependent [25]. Messinis and associates [26] found a significant reduction in leptin concentration 4 days after bilateral ovariectomy in normal cycling women. The effect of graded doses of human leptin on estradiol and progesterone concentrations in culture media of human granulosa-lutein cells obtained from the follicular fluid of women undergoing in vitro fertilization was studied by Ghizzoni and co-workers [27]. Leptin suppressed estradiol secretion by human granulosa-lutein cells but did not modify the elevation of estradiol concentrations when these cells were co-incubated with increasing concentrations of human chorionic gonadotropin and insulin-like growth factors. These studies indicate that a feedback loop might exist between estrogens and leptin, the estrogens inducing directly and/or indirectly the secretion of leptin, while leptin inhibits estrogen synthesis.

Circumstantial evidence suggests that ovarian hormones might affect leptin production in a variable way. Machinal-Quelin and colleagues examined serum leptin levels and leptin mRNA expression in rat adipose tissue during normal estrous cycles in intact rats and during artificial estrous cycles in ovariectomized rats. They found that estrogens induced increased serum leptin concentrations and leptin mRNA expression in adipose tissue [28].

Are changes in body weight mediated by estrogens? Ovariectomized female rats develop obesity. To investigate whether leptin is a key factor in the development of obesity resulting from ovariectomy, Shimomura's group investigated body weight changes after ovariectomy in leptin-dencient genetically obese mice with leptin supplementation and in lean mice without leptin supplementation. Retroperitoneal white adipose tissue weight was increased significantly only in lean mice without leptin treatment, and not in leptin-deficient obese mice treated with leptin [29]. This suggests that reduction of circulating leptin levels by ovariectomy might play an important role in the increases of acute phase body weight gain. Ainslie and associates examined whether the altered energy balance in ovariectomized female rats was associated with inadequate circulating leptin levels, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression or increased hypothalamic neuropeptide Y (NPY). Obesity was not associated with hypoleptinemia or decreased ob expression but it was associated with insensitivity to central leptin administration, while NPY concentration in the paraventricular nucleus of the hypothalamus was elevated [30].

Leptin exerts its action by modifying the synthesis and secretion of a large number of both anorexigenic and orexigenic neuropeptides. Leptinsensitive neurons include those that produce NPY, Agouti- related protein (AGRP), melaninconcentrating hormone, neurotensin, cocaineand amphetamine-related transcript, corticotropinreleasing hormone and melanocyte-stimulating hormone [6]. Insensitivity to central leptin administration and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency [30].

Gower and co-workers measured leptin concentrations in normally cycling women in an untreated spontaneous cycle, in a cycle treated with estradiol (skin patches) and in a cycle treated with estradiol plus progesterone (intravaginally). Women treated with estradiol plus progesterone had elevated serum leptin concentrations in daily blood samples. When estradiol was administered alone, leptin concentrations were not affected [31]. When women with normal cycles were studied during the fourth postoperative day period after bilateral ovariectomy to investigate the relationship between gonadal steroids and leptin levels, a significant reduction in leptin concentrations was found. There was a positive correlation of leptin values with BMI, estradiol and progesterone before and after the operation [26]. The same team studied leptin levels in ovariectomized normal women treated with estradiol plus progesterone. They found that HRT prevented the ovariectomy-induced decrease of leptin levels [32].

Ghrelin is a recently discovered orexigenic gastric hormone (a peptide of 28 amino acids) whose production is induced by lack of food in the stomach [33]. Ghrelin increases food intake in humans and rodents. The ghrelin knockout mouse is not anorectic and this appears as a remarkable difference from the leptin knockout mouse [34]. Ghrelin controls energy balance, enhancing fat mass deposition and food intake through activation of the hypothalamic nuclei and the promotion of NPY and AGRP expression; since it stimulates weight gain, ghrelin is considered a possible important factor in the etiology of obesity [35]. Ghrelin levels are low in morbidly obese individuals compared with lean persons. Plasma ghrelin levels increase during dieting, leading to an orexigenic signal, which could explain the lack of success in dieting among morbidly obese individuals [33]. To study whether estrogen modulates ghrelin expression, Matsubara and associates investigated the effects of ovariectomy on the number of ghrelin-immunopositive and -expressing cells, ghrelin mRNA levels and plasma ghrelin concentrations in 4- and 9-weck-old female rats. Results suggested that estrogen is involved in the regulation of ghrelin expression [36]. In a doubleblind, placebo-controlled trial, Nikander and coinvestigators studied the effects of isolated isoflavonoids (114mg/dl) on ghrelin in 56 non-diabetic postmenopausal women with a history of breast cancer. Changes in ghrelin levels differed during the isoflavonoid and placebo regimens. The authors concluded that isoflavonoids might reduce ghrelin levels, and thus hunger and weight [37].

Menopause-related obesity

During menopause there is a rise in FSH and LH levels and a fall in estrogen levels [2]. FSH levels rise earlier than LH levels. In postmenopausal women, the higher concentration of FSH as compared with LH results from the decrease of inhibin secretion by the ovary. Furthermore, to this effect may contribute the fact that FSH is cleared from plasma less rapidly than LH and the possible loss of estradiol feedback on LH production [3].

Recent evidence has suggested that changes in energy expenditure, body composition and regional body fat may be influenced and even accelerated during the menopause transition [2]. Several studies suggest that women gain body weight and fatness with age.

Are changes in body composition after menopause caused by the decrease of circulating estrogen? In the past it has been proposed that changes in body composition that occur with aging in women begin at or near the onset of menopause and progress linearly with time [2]. Menopause tends to be associated with an increased risk of obesity and a shift to an abdominal fat distribution (android type of obesity) with associated increased health risks. Changes in body composition at menopause might be caused by the decrease in circulating estrogen [15].

Estrogen deficiency appears to accelerate abdominal fat accumulation. The menopause transition induces dramatic reductions in ovarian estrogen levels, whereas the adrenal glands continue to secrete androgen precursors. These inactive steroid precursors are aromatized to estrogens in adipose tissue. However, the levels of circulating estrogens during menopause decrease significantly compared with those during reproductive period of life. More specifically, abdominal adiposity has been associated with a more androgenic profile, with increased free testosterone levels and lower sex hormone-binding globulin (SHBG) levels in pre- and postmenopausal women. The dramatic modifications in the dynamics of estrogens, free androgens and SHBG, or the relative androgenicity, have been suggested to be responsible for changes in body fat distribution during this period [15]. The relative increase in the androgen/estrogen ratio is likely to be important for the fat distribution shift [14].

To estimate the effects of climacteric modifications on body weight and fat distribution, Gambacciani and colleagues investigated three healthy groups of women using dual-energy X-ray absorptiometry. Body weight and BMI were significantly higher in perimenopausal and postmenopausal than in premenopausal women. Mean total body fat, percentage of fat with respect to soft tissue, and amount of fat tissue and percent regional fat with respect to total fat tissue were higher in the trunk and arm regions in perimenopausal and postmenopausal women than in premenopausal women [38].

Is leptin mediating changes in body composition after menopause? Most studies have observed no differences in serum leptin levels between pre- and postmenopausal women, while others showed either decreased or increased leptin levels. Hadji and coworkers evaluated the influence of menopausal status, serum estradiol and BMI on serum leptin concentrations in a large sample of pre- and postmenopausal women. They found that leptin levels were much higher in pre- and postmenopausal obese women than in corresponding normalweight controls, suggesting that leptin level is not influenced by menopausal status or serum estradiol level [39].

Hormone replacement therapy and body fat gain

Some studies have found th\at HRT has no effect on body weight and body composition changes, whereas in other studies HRT increased body weight, promoted gynoid fat distribution and prevented the abdominal shift of body fat commonly observed after menopause [40].

It has been suggested that estrogen depletion may be related to the increased deposition of body fat in the intra-abdominal region in postmenopausal women. Premenopausal women, in contrast to postmenopausal women, have higher lipolytic activity in the abdominal adipose tissue and higher activity of lipoprotein lipase in the femoral adipose tissue. Menopause-induced estrogen depletion could, therefore, influence these mechanisms and lead to a relative increase in abdominal fat [2]. Davies and colleagues evaluated total body weight change in midlife women with respect to menopausal status and estrogen administration. They found that long-term total body weight trajectory at midlife was not influenced appreciably by either cessation of ovarian function or HRT [41]. On the other hand, both general and abdominal obesity, as well as loss of skeletal muscle, is accelerated following menopause. Sex hormone deficiency plays an important role in lifestyle changes. Through the climacteric period short-term HRT with or without androgens preserves muscle mass and inhibits the appearance of obesity [42]. Jensen and associates investigated the influence of HRT on weight changes, body composition and bone mass in early postmenopausal women. During the 5-year follow-up, body weight increased less in women randomized to HRT than in non-randomized women. The smaller weight gain in women on was almost entirely caused by a lesser gain in fat [43]. Arabi's group compared the 2-year effects of tibolone with those of combined 17β-estradiol and norethisterone acetate (E^sub 2^ + NETA) treatment on body composition and bone mass density (BMD) in postmenopausal women. In these women both fat mass and lean mass are related to BMD, the relationship to lean mass being the strongest. During treatment with tibolone and E^sub 2^ + NETA an increase in lean mass and a decrease in android fat were observed [40]. In a Cochrane meta-analysis of 22 randomized controlled trials, the objective was to evaluate the effect of unopposed estrogen or combined estrogen and progestogen HRT on the weight gain and body fat distribution of perimenopausal and postmenopausal women. The study concluded that there was no statistically significant difference in mean BMI increase between those receiving estrogen, those not receiving estrogen-progestogen and non-users of HRT. Thus, the authors concluded that there is no evidence of any effect of unopposed estrogen or combined estrogen- progestogen on body weight, suggesting that these regimens do not lead to weight gain other than that usually gained during menopause [44].

The effects of tibolone on body composition were determined by employing bioelectrical impedance analysis. Compared with placebo, tibolone significantly increased fat-free mass and total body water while fat mass remained unchanged [45]. Shadoan and colleagues studied the effects of tibolone, CEE and CEE + medroxyprogesterone acetate (MPA) on body composition and body weight of cynomolgus monkeys subject to surgical menopause [46]. Compared with controls, body weight increased significantly and abdominal soft tissue mass was greater in all but the CEE-treated groups. Hormone therapy with CEE + MPA or tibolone resulted in increased abdominal soft tissue.

Hanggi and associates compared the effects of tibolone administration versus sequential oral or transdermal estradiol combined with dydrogesterone on body composition and weight. Oral estradiol + dydrogesterone and tibolone administration prevented total body fat change whereas transdermal estradiol + oral dydrogesterone and tibolone prevented lean mass changes. Furthermore, oral estradiol + dydrogesterone prevented the shift to central (android) fat distribution [47].

In the past few years, raloxifene has been introduced as an anti- osteoporotic alternative to HRT. MeIi and co-workers found that leptin was significantly higher in rats 7 weeks after ovariectomy than in controls, in parallel with body fat mass increase. Both 7 and 22 weeks of estrogen replacement reversed the ovariectomy- induced increase in food intake, body weight and fat mass [48]. Treatment of ovariectomized rats with raloxifene reversed the ovariectomy-induced increases in food intake, body weight and fat mass. In ovariectomized rats without raloxifene treatment, expression of the leptin receptor was increased in adipose tissue at 7 weeks and decreased in both the hypothalamus and adipose tissue at 22 weeks. These effects were reversed by raloxifene treatment [48]. In another study the hypothesis that both raloxifene and estrogen improve insulin sensitivity in postmenopausal women was tested. In contrast to estrogen, raloxifene decreases insulin sensitivity in postmenopausal women [49].

Hormone replacement therapy and leptin

Subcutaneous 17bgr;-estradiol administration results elevated leptin mRNA levels in adipose tissue and elevated plasma leptin levels in female rats compared with male rats. Subcutaneous administration of 17β-estradiol to female rats for 2 days significantly elevated leptin mRNA levels in adipose tissue compared with vehicle controls. Thus, it seems that 17β-estradiol can regulate leptin gene expression and secretion, providing a better understanding of the possible anorectic effect of 17β- estradiol [50]. However, because of species differences regarding the role of leptin, it is difficult to extrapolate data from rodents to human physiology.

Serum leptin levels increased in postmenopausal women treated with short-term HRT independently of changes in fat mass; in the same women, progesterone administration alone did not influence leptin levels [51]. In obese and non-obese postmenopausal women studied before and after HRT administration, plasma leptin levels showed an increase following treatment that was more pronounced in obese than in non-obese women [52]. The administration of HRT to ovariectomized women starting 15 days after surgery did not modify leptin levels, suggesting that in humans estrogens may not exert an important role on leptin secretion. Leptin levels and BMI remained unmodified after 6 months of HRT in ovariectomized women, whereas leptin levels increased significantly while a trend towards a higher BMI was noted in untreated ovariectomized women, suggesting that HRT may prevent changes in fat distribution and leptin levels occurring with surgical menopause.

To determine the influence of HRT, insulin and fat distribution on circulating leptin levels in postmenopausal women, Gower and associates compared HRT-treated postmenopausal women and untreated controls. Multiple linear regression analysis indicated that total fat mass, lean mass and fasting insulin, but not HRT, were significant determinants of serum leptin levels [31]. Thomas and colleagues studied 137 prcmenopausal and 212 postmenopausal women, of whom 47 were on HRT. They concluded that fat mass, lean mass and insulin levels were the strongest predictors of leptin levels in all groups [53].

Table III. Summary of clinical studies investigating the effect on serum leptin levels of hormone replacement therapy (HRT) and alternative forms of therapy in postmenopausal women.

Recently we evaluated plasma leptin levels in obese and non- obese postmenopausal women before and after HRT with CEE, CEE+ MPA or tibolone. Serum leptin concentrations at baseline were significantly higher in obese postmenopausal women than in non- obese women. After 6 months of therapy plasma leptin levels did not differ significantly between obese and non-obese postmenopausal women on any of these three different types of treatment [54]. In a randomized placebo-controlled study in postmenopausal women with type 2 diabetes mellitus treated with transdermal E^sub 2^ + NETA, no significant alterations in fibrinogen, tissue plasminogen activator, fibrin D-dimer, very-low-density lipoprotein cholesterol, low-density lipoprotein cholesterol or leptin levels were found [55]. On the other hand, some authors have found no change in leptin levels and BMI following low-dose transdermal HRT [56]. In a double- blind placebo-controlled study, low doses of transdermal estradiol did not influence fasting leptin levels and BMI. It is possible that different doses of estradiol exert a more pronounced effect on circulating leptin [57].

In a 1-year comparative study in postmenopausal women treated with oral or transdermal E^sub 2^ + NETA, Laivuori and co-workers evaluated the effect of these regimens on circulating concentrations of leptin. Neither oral nor transdermal E^sub 2^ + NETA caused any significant change in plasma leptin concentrations or BMI after 2, 6 and 12 months of treatment [58]. Serum leptin levels were elevated in untreated postmenopausal women when compared with premenopausal women of similar BMI, possibly as a consequence of the increase of fat mass [59]. The same group evaluated body composition, total and percent fat mass versus lean mass and serum leptin levels in healthy HRTtreated and untreated postmenopausal women during a prospective longi-tudinal study. Untreated postmenopausal women showed an increase in total and percent fat mass and a centralization of fat distribution. In women taking HRT, serum leptin levels did not change significantly throughout the study period [60].

We have recently investigated the influence of tibolone on serum leptin levels in postmenopausal women. We found that leptin levels were increased in all women with elevated BMI and no statistically significant change in serum leptin associated with tibolone administration independently of age and treatment duration [61]. To our knowledge, no data exist on leptin levels in postmenopausal women treate\d with raloxifene.

Table III summarizes clinical studies studying the effect of HRT regimens on serum leption levels.

Conclusions

There is no consensus regarding the role of HRT in modulating visceral obesity. Some studies have shown HRT to have no effect on body weight and changes in body composition. In other studies HRT increased body weight, promoted gynoid fat distribution and prevented the shift of body composition to central obesity commonly observed after the menopause.

Leptin is an adipocyte-derived hormone. Body adiposity has been shown to be a major determinant of circulating leptin. Obesity is associated with elevated plasma leptin levels but insulin sensitivity may be an additional determinant of circulating leptin. The effect of HRT on leptin levels is controversial. The major problem encountered during administration of hormone therapy seems to be the timing of HRT initiation. Apparently, through known and as yet unknown mechanisms affecting body metabolism, menopause contributes to increased adipose tissue. The latter is paralleled by an increase in leptin levels. In vitro and in vivo studies converge to the conclusion that estrogens directly and/or indirectly stimulate leptin secretion. However, HRT administration to menopausal women seems to keep body weight stable. Thus, it is difficult to discern the effect of HRT administration on leptin levels during the menopause because, on one hand, estrogen administration contributes to the direct increase of leptin and, on the other, leptin decreases due to body weight decrease.

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ARETI AUGOULEA, GEORGE MASTORAKOS, IRENE LAMBRINOUDAKI, GEORGE CHRISTODOULAKOS, & GEORGE CREATSAS

Second Department of Obstetrics and Gynecology, Aretaieion Hospital, University of Athens, Athens, Greece

Correspondence: G. Christodoulakos, 3 Neofytou Douka Street, Athens, GR-10674 Greece. Tel/Fax: 302108137716. E-mail: ilambrinoudaki@hotmail.com

Copyright CRC Press Apr 2005

Source: Gynecological Endocrinology

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