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From the Department of Endocrinology and Medical Sciences and Center of Excellence for Biomedical Research, University of Genova, Italy.
| Correspondence to: Dr Eugenia Resmini, Department of Endocrinology and Medical Sciences, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy (e-mail: resminieugenia{at}libero.it). |
| Received for publication January 14, 2008; accepted for publication April 17, 2008. |
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Abstract |
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Key words: Cardiovascular risk, sexual hormones, metabolic parameters
Gender differences in adiponectin levels are documented during the progression of puberty and seem linked to serum androgen levels (Bottner et al, 2004). In fact, testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes (Page et al, 2005; Seftel et al, 2005). Moreover, androgen-induced hypoadiponectinemia may be related to the high risks of insulin resistance and atherosclerosis in men (Nishizawa et al, 2002). Increased levels of androgens postmenopause and low sex hormone binding globulin (SHBG) are connected with decreased production of adiponectin (Chu et al, 2006). It has been also demonstrated that testosterone may decrease adiponectin levels in female-to-male transsexuals (Berra et al, 2006). In contrast, recent data show that sex differences in circulating adiponectin levels in older adults cannot be explained by sex hormone regulation (Laughlin et al, 2007).
Sexual dimorphism in serum leptin levels has been described as well, with higher concentrations in women than in men, even when adjusted for body fat (Saad et al, 1997; Pardo et al, 2004). These observations are potentially important for the understanding of differences between men and women in regulation of food intake, weight gain, and body fat distribution. Androgen supplementation decreases serum leptin concentrations, whereas androgenic suppression increases serum leptin levels in healthy men, independently from changes in the body fat mass (Elbers et al, 1997; Hislop et al, 1999). In rats, testosterone plays a role in plasma leptin turnover by increasing leptin clearance rate and shortening plasma leptin half-life (Castrogiovanni et al, 2003). The fact that leptin levels are always higher in females, even after correcting for body fat content, suggests that the interaction between adipose tissue and the reproductive system is modulated by sex hormones in a different way in males and females (Casabiell et al, 2001). It seems that adipocytokines may represent the link between postmenopausal hormonal changes, excess of visceral fat, and increased risk of cardiovascular diseases.
Sexual dimorphism in leptin levels is not simply explained as differences in total adiposity between genders; there are genes, expressed differently depending on gender, that influence variation in serum leptin (Martin et al, 2002). Moreover, the sexual dimorphism in leptin concentrations appears to reflect the effect of circulating concentrations of gonadal steroids (Rosenbaum et al, 2001).
The sexual dimorphism in these 3 hormones could be important for understanding the differences between males and females in the regulation of food intake, weight gain, body fat distribution, and cardiovascular risk. However, it is still unclear how endogenous, as well as exogenous, sex hormones may regulate the circulating levels of these factors. Transsexual subjects during hormonal treatment may represent an ideal model to ascertain the role of exogenous sex hormones on these parameters. Since few data are available on the role of sex hormone therapies on the level of these 3 factors, we evaluated leptin, ghrelin, and adiponectin levels in transsexuals during hormonal treatments.
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Materials and Methods |
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The duration of exposure to cross-sex hormone treatment in transsexual patients was 9 ± 2.31 years for M-to-F subjects and 10 ± 1.48 years for F-to-M subjects. The study protocol was approved by the local ethical committee, and a written informed consent was obtained from all subjects.
After overnight fasting, transsexuals and controls underwent blood sampling for measurement of serum leptin, ghrelin, adiponectin, insulin, glucose, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. In control females, LH, FSH, estradiol, and testosterone were measured in follicular phase.
Two M-to-F patients who previously underwent surgery for gender reassignment were receiving only estradiol during the study. Thirteen M-to-F patients, 3 of whom previously underwent surgery for gender reassignment, were treated with anti-androgen (12 with ciproterone acetate, 100 mg/d and 1 with spironolactone, 200 mg/d) and estrogen (estradiol hemihydrate transdermal or oral tablets, 4 mg/d). As concomitant treatments, 2 were in therapy with antidepressive drugs and 1 with thyroxin for nodular goiter. The time elapsed between surgery for gender reassignment and the present study was 6.80 ± 1.91 years.
One F-to-M patient previously underwent surgery for gender reassignment 9 years before the present study. All F-to-M patients were receiving depot testosterone (250 mg intramuscularly every 21 days); 2 subjects were injected with testosterone enantate and the remaining subjects with an androgenic preparation for intramuscular administration containing 4 different esters of the natural hormone testosterone (testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg). The hormonal samples were taken about midway between 2 injections of testosterone depot; therefore, the hormonal values were comparable among the subjects. As concomitant treatments, 1 patient was taking thyroxin for nodular goiter.
Analytical Methods
Serum leptin was assayed by radioimmunoassay (DRG Diagnostics GmbH,
Marburg, Germany). Sensitivity of the method was 0.5 µg/L. Intra-assay and
interassay percent coefficents of variation (CV) were lower than 3.9% and
4.7%, respectively.
Serum ghrelin levels were measured by a commercial radioimmunoassay (Phoenix Pharmaceuticals, Belmont, California) that uses 125I-labeled bioactive ghrelin as a tracer and a rabbit polyclonal antibody raised against full-length octanoylated human ghrelin that recognized both acylated and desacylated ghrelin. Sensitivity of the method was 10 pg/mL. Intra-assay CV was 8.7%, and interassay CV was 11.2 %.
Serum adiponectin levels were measured in duplicate by commercial radioimunoassay (DRG Diagnostics). Sensitivity of the method was 1 ng/mL. Intra-assay CV was 3.9%, and interassay CV was 8.4%. All measurements of leptin, ghrelin, and adiponectin were made in duplicate in the same batch. After separation, serum samples were stored at –20°C until analysis.
Serum glucose and insulin concentrations were measured respectively by enzymatic method (Randox, London, United Kingdom) and sandwich immunoradiometric assay (Immunotech SA, Marseille, France).
Insulin sensitivity was estimated according to the homeostasis model assessment of insulin resistance (HOMA-IR) (Matthews et al, 1985). The HOMA cutoff point of >2.5 indicates the presence of insulin resistance in adults. Estradiol and total testosterone were measured with a commercial chemiluminescent assay (Immulite 2000; DPC, Los Angeles, California), and FSH and LH were measured with a commercial immunoenzymometric assay (IEMA; Radim, Rome, Italy).
Statistical Analysis
Statistical analysis of data was carried out by SPSS software (version 12
for Windows; SPSS, Bologna, Italy). The analysis was performed using the
Mann-Whitney test for nonparametric data both for the comparison between
patients and controls and within each group. The quantitative variables were
expressed as means ± SEM.
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Results |
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Leptin levels were significantly lower in group 1 compared with group 2 (P = .004) and group 3 (P = .01), whereas no differences were found between the other groups. Conversely, adiponectin levels were significantly higher in group 3 compared with group 4 (P = .03), whereas no differences were found between the other groups.
No correlations between the levels of estrogen and testosterone with those of ghrelin, adiponectin, and leptin in the 2 groups of transsexuals were found.
BMI and sex hormone evaluations are reported in the Table, whereas the distribution of insulin, leptin, ghrelin, adiponectin, as well as HOMA in the 4 groups are graphically illustrated in Figure 1.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Moreover, in the F-to-M group there was a strong variability in leptin levels (Figure 1E). Indeed, a number of F-to-M subjects showed leptin levels similar to those measured in females, whereas other F-to-M subjects had leptin levels similar to those in males. This could be related to the previously known individual variability in the response to androgen administration. Moreover, there are a lot of factors that cause gender differences in leptin levels, both genetic (Martin et al, 2002) and hormonal (Casabiell et al, 2001; Rosenbaum et al, 2001). However, taken together, these data suggest that estrogen and antiandrogen therapies may increase leptin levels, which may be in line with other data showing that androgens reduce leptin levels (Elbers et al, 1997; Saad et al, 1997; Hislop et al, 1999; Castrogiovanni et al, 2003; Pardo et al, 2004).
In the literature, there are conflicting data regarding adiponectin and sex
hormone influence (Page et al,
2005; Seftel et al, 2005;
Laughlin et al, 2006;
Laughlin et al, 2007).
However, males seem to have lower adiponectin levels than females, and this
androgen-induced adiponectin deficiency (hypoadiponectinemia) may contribute
to the higher cardiovascular risk in males. Hypoadiponectinemia is an
independent risk factor for endothelial dysfunction, hypertension, coronary
heart disease, myocardial infarction, and other cardiovascular complications
(Giannessi et al,
2007).
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F-to-M transsexuals could have an increase of their cardiovascular risk in terms of changes in body composition (Elbers et al, 2003). Moreover hyperandrogenism, usually resulting from PCOS, is associated with an unfavorable cardiovascular risk (Gooren et al, 2008). Association of hypoadiponectinemia with metabolic syndrome in patients with PCOS is reported, and adiponectin as an endogenous biologically relevant modulator of vascular remodeling may have a role in the development of metabolic syndrome in PCOS patients (Gulcelik et al, 2008).
The evidence of significantly lower adiponectin levels in F-to-M transsexuals in comparison with M-to-F patients confirms the data from the literature showing that androgens decrease plasma adiponectin levels. Indeed, F-to-M transsexuals have lower adiponectin levels compared with males. Subjects with low adiponectin levels are considered at high cardiovascular risk because adiponectin plays a role in the pathogenesis of atherosclerosis, especially in obese and insulin-resistant patients (Dunajska et al, 2004). Therefore, F-to-M transsexuals may potentially develop a higher cardiovascular risk due to their low adiponectin levels, even lower than males, as a consequence of the exogenous androgen administration. However, the clinical consequences associated with the lower adiponectin levels might need more time to become evident. Indeed, these subjects maintain normal cholesterol and triglycerides levels, as well as HOMA, probably due to the short duration of exposure to cross-sex hormones.
In contrast, estrogen therapy may increase adiponectin levels in M-to-F transsexuals. Hypoandrogenemia in males and hyperandrogenemia in females are associated with increased risk of coronary artery disease, especially when there is the coexistence of visceral obesity, insulin resistance, low high-density lipoprotein (HDL) cholesterol, elevated triglycerides, low LDL, and plasminogen activator inhibitor (PAI-1; Eckardstein and Wu, 2003).
Our results indicate that exogenous sex hormones do not influence ghrelin levels in transsexuals during treatments. These results are apparently in contrast with the few data in the literature about gender differences and the influence of estrogen and/or androgen treatment on ghrelin levels (Gambineri et al, 2003; Pagotto et al, 2003; Kellokoski et al, 2005). Indeed, in PCOS, circulating ghrelin and androgen levels are inversely related (Panidis et al, 2005). Therefore, we expected F-to-M to display lower levels of ghrelin than normal females. However, the high variability in ghrelin levels in our female control group might account for the lack of a significant difference between the 2 populations in this study. In fact, if we consider the median in Figure 1C (the middle line of the boxplot), we could speculate ghrelin is higher in females compared with both F-to-M transsexuals and males. Another potential explanation might be the relative short time of exposure to androgens of F-to-M transsexuals. However, the data on sexual dimorphism of ghrelin are scant, and further studies are warranted to clarify this aspect.
In conclusion, our data confirm the sexual dimorphism in serum leptin levels in normal subjects and show an increase in levels in M-to-F transsexuals. The lower adiponectin levels in females treated with androgens confirm the literature data that androgens decrease plasma adiponectin levels and suggest that F-to-M transsexual subjects could have a higher cardiovascular risk factor due to the lower adiponectin levels. Ghrelin does not display sexual differences and it seems not to be influenced by exogenous sex hormone administration. However, further studies are needed to shed light on how sex steroids may regulate these hormones.
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Footnotes |
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Berra M, Armillotta F, D'Emidio L, Costantino A, Martorana G, Pelusi G, Meriggiola MC. Testosterone decreases adiponectin levels in female to male transsexuals. Asian J Androl. 2006; 8: 725 –729.[CrossRef][Medline]
Bottner A, Kratzsch J, Muller G, Kapellen TM, Bluher S, Keller E,
Bluher M, Kiess W. Gender differences of adiponectin levels develop during the
progression of puberty and are related to serum androgen levels. J
Clin Endocrinol Metab. 2004; 89: 4053
–4061.
Casabiell X, Pineiro V, Vega F, De La Cruz LF, Dieguez C, Casanueva FF. Leptin, reproduction and sex steroids. Pituitary. 2001; 4: 93 –99.[CrossRef][Medline]
Castrogiovanni D, Perello M, Gaillard RC, Spinedi E. Modulatory role of testosterone in plasma leptin turnover in rats. Endocrine. 2003; 22: 203 –210.[CrossRef][Medline]
Chu MC, Cosper P, Orio F, Carmina E, Lobo RA. Insulin resistance in postmenopausal women with metabolic syndrome and the measurements of adiponectin, leptin, resistin, and ghrelin. Am J Obstet Gynecol. 2006;194: 100 –104.[CrossRef][Medline]
Dunajska K, Milewicz A, Jedrzejuk D, Szymczak J, Kuliczkowski W, Salomon P, Bialy D, Poczatek K, Nowicki P. Plasma adiponectin concentration in relation to severity of coronary atherosclerosis and cardiovascular risk factors in middle-aged men. Endocrine. 2004; 25: 215 –221.[CrossRef][Medline]
Eckardstein A, Wu FC. Testosterone and atherosclerosis. Growth Horm IGF Res . 2003; 13: 72 –84.[CrossRef]
Elbers JM, Asscheman H, Seidell JC, Frölich M, Meinders AE,
Gooren LJ. Reversal of the sex difference in serum leptin levels upon
cross-sex hormone administration in transsexuals. J Clin Endocrinol
Metab. 1997;82: 3267
–3270.
Elbers JM, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJ. Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol. 2003; 58: 562 –571.[CrossRef][Medline]
Gambineri A, Pagotto U, De Lasio R, Meriggiola MC, Costantino A, Patton L, Pelusi C, Pelusi G, Pasquali R. Short-term modification of sex hormones is associated with changes in ghrelin circulating levels in healthy normal-weight men. J Endocrinol Invest. 2005; 28: 241 –246.[Medline]
Gambineri A, Pagotto U, Tschop M, Vicennati V, Manicardi E, Carcello A, Cacciari M, De Iasio R, Pasquali R. Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome. J Endocrinol Invest. 2003; 26: 629 –634.[Medline]
Giannessi D, Maltinti M, Del Ry S. Adiponectin circulating levels: a new emerging biomarker of cardiovascular risk. Pharmacol Res. 2007;56: 459 –467.[CrossRef][Medline]
Gooren LJ, Giltay EJ, Bunck MC J. Long-term treatment of
transsexuals with cross-sex hormones: extensive personal experience.
J Clin Endocrinol Metab. 2008; 93: 19
–25.
Greenman Y, Golani N, Gilad S, Yaron M, Limor R, Stern N. Ghrelin secretion is modulated in a nutrient- and gender-specific manner. Clin Endocrinol. 2004; 60: 382 –388.[CrossRef][Medline]
Gulcelik NE, Aral Y, Serter R, Koc G. Association of hypoadiponectinemia with metabolic syndrome in patients with polycystic ovary syndrome. J Natl Med Assoc. 2008 Jan; 100: 64 –68.[Medline]
Hislop MS, Ratanjee BD, Soule SG, Marais AD. Effects of anabolic-androgenic steroid use or gonadal testosterone suppression on serum leptin concentration in men. Eur J Endocrinol. 1999; 141: 40 –46.[Abstract]
Kellokoski E, Poykko SM, Karjalainen AH, Ukkola O, Heikkinen J,
Kesaniemi YA, Horkko S. Estrogen replacement therapy increases plasma ghrelin
levels. J Clin Endocrinol Metab. 2005; 90: 2954
–2963.
Laughlin GA, Barrett-Connor E, May S. Sex-specific association of the androgen to oestrogen ratio with adipocytokine levels in older adults: the Rancho Bernardo Study. Clin Endocrinol. 2006; 65: 506 –513.[CrossRef][Medline]
Laughlin GA, Barrett-Connor E, May S. Sex-specific determinants of serum adiponectin in older adults: the role of endogenous sex hormones. Int J Obes. 2007; 31: 457 –465.[CrossRef][Medline]
Martin LJ, Mahaney MC, Almasy L, MacCluer JW, Blangero J, Jaquish CE, Comuzzie AG. Leptin's sexual dimorphism results from genotype by sex interactions mediated by testosterone. Obes Res. 2002; 10: 14 –21.[Medline]
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28: 412 –419.[CrossRef][Medline]
Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H,
Nagaretani H, Matsuda M, Kondo H, Furuyama N, Kihara S, Nakamura T, Tochino Y,
Funahashi T, Matsuzawa Y. Androgens decrease plasma adiponectin, an
insulin-sensitizing adipocyte-derived protein.
Diabetes. 2002;51: 2734
–2741.
Page ST, Herbst KL, Amory JK, Coviello AD, Anawalt BD, Matsumoto
AM, Bremner WJ. Testosterone administration suppresses adiponectin levels in
men. J Androl. 2005; 26: 85
–92.
Pagotto U, Gambineri A, Pelusi C, Genghini S, Cacciari M, Otto B,
Castaneda T, Tschop M, Panidis D, Farmakiotis D, Koliakos G, Rousso D, Kourtis
A, Katsikis I, Asteriadis C, Karayannis V, Diamanti-Kandarakis E. Comparative
study of plasma ghrelin levels in women with polycystic ovary syndrome, in
hyperandrogenic women and in normal controls. Hum
Reprod. 2005;20: 2127
–2132.
Pardo IM, Geloneze B, Tambascia MA, Pereira JL, Barros Filho AA. Leptin as a marker of sexual dimorphism in newborn infants. J Pediatr. 2004;80: 305 –308.
Pasquali R. Testosterone replacement therapy restores normal
ghrelin in hypogonadal men. J Clin Endocrinol Metab. 2003; 88: 4139
–4143.
Rosenbaum M, Pietrobelli A, Vasselli JR, Heymsfield SB, Leibel RL. Sexual dimorphism in circulating leptin concentrations is not accounted for by differences in adipose tissue distribution. Int J Obes Relat Metab Disord. 2001;25: 1365 –1371.[CrossRef][Medline]
Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian
R, Jinagouda SD, el-Tawil K, Rude RK, Kamdar V. Sexual dimorphism in plasma
leptin concentration. J Clin Endocrinol Metab. 1997; 82: 579
–584.
Seftel AD. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Urol. 2005;174: 1045 –1046.[Medline]
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