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Journal of Andrology, Vol. 29, No. 5, September/October 2008
Copyright E American Society of Andrology
Leptin, Ghrelin, and Adiponectin Evaluation in Transsexual
Subjects During Hormonal Treatments
EUGENIA RESMINI, GABRIELLA ANDRAGHETTI, ALBERTO REBORA, RENZO CORDERA,
LARA VERA, MASSIMO GIUSTI, FRANCESCO MINUTO, AND DIEGO FERONE
From the Department of Endocrinology and Medical Sciences and Center of Excellence for Biomedical Research,
University of Genova, Italy.
ABSTRACT: Gender differences in leptin, ghrelin, and adiponectin 2 (P 5 .04) and group 3 (P 5 .01); no differences were recorded
levels have been described in a normal population. This is important between the other groups. Adiponectin levels were significantly
for understanding differences between males and females in the higher in group 3 compared with group 4 (P 5 .03). No differences
regulation of food intake, weight gain, body fat distribution, and were found between the 4 groups for ghrelin levels. In conclusion,
cardiovascular risk. It is unclear how endogenous and exogenous our data confirm the sexual dimorphism in serum leptin levels in
sex hormones may regulate circulating levels of these factors. normal subjects and demonstrate an increase in M-to-F transsexu-
Transsexuals during hormonal treatment may represent an ideal als. While ghrelin does not show any sexual differences and seems
model to ascertain the role of exogenous sex hormones on these not to be influenced by exogenous sex hormone administration, the
parameters. In this study, our objective was to evaluate adiponectin, lower adiponectin levels in F-to-M transsexuals during treatment
ghrelin, and leptin levels in transsexual subjects during hormone confirm that androgens may decrease plasma adiponectin levels.
therapy and to compare the results of males and females. Subjects This latter observation suggests that F-to-M transsexual patients
were 26 nondiabetic transsexuals, which included 15 male-to-female could have a higher cardiovascular risk.
(M-to-F, group 3) and 11 female-to-male (F-to-M, group 4) Key words: Cardiovascular risk, sexual hormones, metabolic
individuals, and 29 age- and BMI-matched controls, which included parameters.
15 males (group 1) and 14 females (group 2). Results showed that J Androl 2008;29:580–585
leptin levels were significantly lower in group 1 compared with group
G ender differences in leptin, ghrelin, and adiponec-
tin values have been described in normal subjects.
It has been shown that ghrelin secretion is sexually
replacement therapy restores normal ghrelin in hypogo-
nadal men (Pagotto et al, 2003).
Gender differences in adiponectin levels are docu-
dimorphic in humans, with women in the late follicular mented during the progression of puberty and seem
stage having higher levels than men (Barkan et al, 2003; linked to serum androgen levels (Bottner et al, 2004). In
Greenman et al, 2004) and that short-term changes of fact, testosterone selectively reduces the high molecular
circulating sex hormones are able to modify ghrelin weight form of adiponectin by inhibiting its secretion
levels (Gambineri et al, 2005). Moreover, in polycystic from adipocytes (Page et al, 2005; Seftel et al, 2005).
ovary syndrome (PCOS), circulating ghrelin and andro- Moreover, androgen-induced hypoadiponectinemia may
gen levels are inversely related (Panidis et al, 2005), and be related to the high risks of insulin resistance and
anti-androgen treatment increases circulating ghrelin atherosclerosis in men (Nishizawa et al, 2002). Increased
levels in obese women with PCOS (Gambineri et al, levels of androgens postmenopause and low sex
2003). Estrogen replacement therapy may increase active hormone binding globulin (SHBG) are connected with
ghrelin levels (Kellokoski et al, 2005). Testosterone decreased production of adiponectin (Chu et al, 2006). It
has been also demonstrated that testosterone may
Supported by Ministero Universita e Ricerca (MIUR) scientifica
` decrease adiponectin levels in female-to-male transsex-
grant 2005062192_003 (F.M.), Fondo per gli Investimenti della uals (Berra et al, 2006). In contrast, recent data show
Ricerca di Base grant RBAU019TMF_001 (F.M.), and Cassa
Risparmio Genova e Imperia (CARIGE) Foundation educational
that sex differences in circulating adiponectin levels in
grant (D.F.). older adults cannot be explained by sex hormone
Correspondence to: Dr Eugenia Resmini, Department of Endocri- regulation (Laughlin et al, 2007).
nology and Medical Sciences, University of Genova, Viale Benedetto Sexual dimorphism in serum leptin levels has been
XV, 6, 16132 Genova, Italy (e-mail: resminieugenia@libero.it).
described as well, with higher concentrations in women
Received for publication January 14, 2008; accepted for publication
April 17, 2008. than in men, even when adjusted for body fat (Saad et al,
DOI: 10.2164/jandrol.108.004952 1997; Pardo et al, 2004). These observations are poten-
580
Resmini et al N Leptin, Ghrelin, and Adiponectin in Transsexuals 581
Table. Clinical and hormonal parameters in transsexual and normal subjects a
M-to-F (n 5 15) F-to-M (n 5 11) Males (n 5 15) Females (n 5 14)
BMI 21.4 6 0.62 21.45 6 0.57 20.21 6 0.51 21.06 6 0.65
COL (TOT) 146.60 6 11.11 142.81 6 18.30 160.35 6 7.54 164.90 6 12.5
LDL 90.30 6 6.67 112.6 6 8.02 99.25 6 4.32 85.24 6 5.32
HDL 55.30 6 3.35 47.4 6 1.98 61.1 6 3.22 79.66 6 7.18
Triglycerides 84.76 6 11.93 78.4 6 5.40 85.41 6 6.35 75.26 6 4.75
LH 5.73 6 3.65 2.95 6 0.62 4.50 6 2.70 5.10 6 2.45
FSH 5.73 6 5.22 7.0 6 2.17 5.23 6 1.25 6.50 6 1.32
Estradiol 56.7 6 10.56 9.09 6 6.53 20.0 6 1.2 77.0 6 3.25
Total testosterone 1.14 6 0.48 4.98 6 0.92 5.30 6 1.20 0.60 6 0.10
Abbreviations: BMI, body mass index; COL (TOT), total cholesterol; FSH, follicle-stimulating hormone; HDL, high-density lipoprotein; LDL, low-
density lipoprotein; LH, luteinizing hormone.
a
Normal values: LH, 0.6–16 UI/L; FSH, 1.5–13 UI/L (follicular phase); total testosterone, 0.2–0.8 ng/mL for females and 3.5–10 ng/mL for
males; estradiol, 20–80 pg/mL for females and ,50 pg/mL for males; total cholesterol, 130–200 mg/L; triglycerides, 40–170 ng/mL; LDL, 0–
120 mg/dL; HDL, .40 mg/dL for males and .45 mg/dL for females. Values are means 6 SEM.
tially important for the understanding of differences evaluated leptin, ghrelin, and adiponectin levels in
between men and women in regulation of food intake, transsexuals during hormonal treatments.
weight gain, and body fat distribution. Androgen
supplementation decreases serum leptin concentrations,
whereas androgenic suppression increases serum leptin Materials and Methods
levels in healthy men, independently from changes in the
body fat mass (Elbers et al, 1997; Hislop et al, 1999). In Subjects and Treatments
rats, testosterone plays a role in plasma leptin turnover by We evaluated 26 nondiabetic transsexual subjects without
increasing leptin clearance rate and shortening plasma dyslipidemia and with normal body mass index (BMI). Fifteen
leptin half-life (Castrogiovanni et al, 2003). The fact that subjects were male-to-female (M-to-F, group 3, mean age
leptin levels are always higher in females, even after 33.21 6 2.1 yrs) transsexuals and 11 were female-to-male (F-
to-M, group 4, mean age 30.90 6 1.81 yrs). We also evaluated
correcting for body fat content, suggests that the
29 age- and BMI-matched subjects, including 15 males (group
interaction between adipose tissue and the reproductive 1) and 14 females (group 2), who served as controls. Control
system is modulated by sex hormones in a different way in females were not using oral estrogen (contraceptive pills). We
males and females (Casabiell et al, 2001). It seems that compared each group of transsexuals with both male and
adipocytokines may represent the link between postmen- female healthy subjects; therefore, each group of transsexuals
opausal hormonal changes, excess of visceral fat, and was compared with 2 control groups (males and females).
increased risk of cardiovascular diseases. Cholesterol, both total and low-density lipoprotein (LDL),
Sexual dimorphism in leptin levels is not simply and triglycerides were normal in all groups (Table).
explained as differences in total adiposity between The duration of exposure to cross-sex hormone treatment in
genders; there are genes, expressed differently depending transsexual patients was 9 6 2.31 years for M-to-F subjects
and 10 6 1.48 years for F-to-M subjects. The study protocol
on gender, that influence variation in serum leptin
was approved by the local ethical committee, and a written
(Martin et al, 2002). Moreover, the sexual dimorphism informed consent was obtained from all subjects.
in leptin concentrations appears to reflect the effect of After overnight fasting, transsexuals and controls underwent
circulating concentrations of gonadal steroids (Rosen- blood sampling for measurement of serum leptin, ghrelin,
baum et al, 2001). adiponectin, insulin, glucose, luteinizing hormone (LH),
The sexual dimorphism in these 3 hormones could be follicle-stimulating hormone (FSH), testosterone, and estradi-
important for understanding the differences between ol. In control females, LH, FSH, estradiol, and testosterone
males and females in the regulation of food intake, were measured in follicular phase.
weight gain, body fat distribution, and cardiovascular Two M-to-F patients who previously underwent surgery for
risk. However, it is still unclear how endogenous, as well gender reassignment were receiving only estradiol during the
study. Thirteen M-to-F patients, 3 of whom previously
as exogenous, sex hormones may regulate the circulating
underwent surgery for gender reassignment, were treated with
levels of these factors. Transsexual subjects during anti-androgen (12 with ciproterone acetate, 100 mg/d and 1
hormonal treatment may represent an ideal model to with spironolactone, 200 mg/d) and estrogen (estradiol hemi-
ascertain the role of exogenous sex hormones on these hydrate transdermal or oral tablets, 4 mg/d). As concomitant
parameters. Since few data are available on the role of treatments, 2 were in therapy with antidepressive drugs and 1
sex hormone therapies on the level of these 3 factors, we with thyroxin for nodular goiter. The time elapsed between
582 Journal of Andrology N September ÙOctober 2008
surgery for gender reassignment and the present study was 6.80
6 1.91 years.
Results
One F-to-M patient previously underwent surgery for
gender reassignment 9 years before the present study. All F- No significant differences were found in HOMA and
to-M patients were receiving depot testosterone (250 mg insulin levels between the 2 groups of transsexuals and
intramuscularly every 21 days); 2 subjects were injected with between transsexuals and controls. Transsexual subjects
testosterone enantate and the remaining subjects with an did not display insulin resistance. Similarly, no statisti-
androgenic preparation for intramuscular administration cally significant differences were found between the 4
containing 4 different esters of the natural hormone testoster- groups for ghrelin levels.
one (testosterone propionate 30 mg, testosterone phenylpro- Leptin levels were significantly lower in group 1
pionate 60 mg, testosterone isocaproate 60 mg, and testoster- compared with group 2 (P 5 .004) and group 3 (P 5
one decanoate 100 mg). The hormonal samples were taken
.01), whereas no differences were found between the
about midway between 2 injections of testosterone depot;
therefore, the hormonal values were comparable among the other groups. Conversely, adiponectin levels were
subjects. As concomitant treatments, 1 patient was taking significantly higher in group 3 compared with group 4
thyroxin for nodular goiter. (P 5 .03), whereas no differences were found between
the other groups.
Analytical Methods No correlations between the levels of estrogen and
Serum leptin was assayed by radioimmunoassay (DRG testosterone with those of ghrelin, adiponectin, and
Diagnostics GmbH, Marburg, Germany). Sensitivity of the leptin in the 2 groups of transsexuals were found.
method was 0.5 mg/L. Intra-assay and interassay percent BMI and sex hormone evaluations are reported in the
coefficents of variation (CV) were lower than 3.9% and Table, whereas the distribution of insulin, leptin,
4.7%, respectively. ghrelin, adiponectin, as well as HOMA in the 4 groups
Serum ghrelin levels were measured by a commercial are graphically illustrated in Figure 1.
radioimmunoassay (Phoenix Pharmaceuticals, Belmont, Cali-
fornia) that uses 125I-labeled bioactive ghrelin as a tracer and a
rabbit polyclonal antibody raised against full-length octanoy-
lated human ghrelin that recognized both acylated and
Discussion
desacylated ghrelin. Sensitivity of the method was 10 pg/mL.
Intra-assay CV was 8.7%, and interassay CV was 11.2 %. The results of our study confirm the gender differences
Serum adiponectin levels were measured in duplicate by in leptin levels. Indeed, females displayed significantly
commercial radioimunoassay (DRG Diagnostics). Sensitivity higher leptin levels than males. There were no differ-
of the method was 1 ng/mL. Intra-assay CV was 3.9%, and ences in leptin levels between females and M-to-F
interassay CV was 8.4%. All measurements of leptin, ghrelin, transsexuals, while male leptin levels were significantly
and adiponectin were made in duplicate in the same batch. lower than in M-to-F transsexuals. These 2 pieces of
After separation, serum samples were stored at 220uC until evidence suggest that leptin levels in M-to-F transsex-
analysis.
uals are comparable to those recorded in females.
Serum glucose and insulin concentrations were measured
respectively by enzymatic method (Randox, London, United
Moreover, in the F-to-M group there was a strong
Kingdom) and sandwich immunoradiometric assay (Immuno- variability in leptin levels (Figure 1E). Indeed, a number
tech SA, Marseille, France). of F-to-M subjects showed leptin levels similar to those
Insulin sensitivity was estimated according to the homeo- measured in females, whereas other F-to-M subjects had
stasis model assessment of insulin resistance (HOMA-IR) leptin levels similar to those in males. This could be
(Matthews et al, 1985). The HOMA cutoff point of .2.5 related to the previously known individual variability in
indicates the presence of insulin resistance in adults. Estradiol the response to androgen administration. Moreover,
and total testosterone were measured with a commercial there are a lot of factors that cause gender differences in
chemiluminescent assay (Immulite 2000; DPC, Los Angeles, leptin levels, both genetic (Martin et al, 2002) and
California), and FSH and LH were measured with a
hormonal (Casabiell et al, 2001; Rosenbaum et al, 2001).
commercial immunoenzymometric assay (IEMA; Radim,
Rome, Italy).
However, taken together, these data suggest that
estrogen and antiandrogen therapies may increase leptin
Statistical Analysis levels, which may be in line with other data showing that
androgens reduce leptin levels (Elbers et al, 1997; Saad
Statistical analysis of data was carried out by SPSS software
(version 12 for Windows; SPSS, Bologna, Italy). The analysis
et al, 1997; Hislop et al, 1999; Castrogiovanni et al,
was performed using the Mann-Whitney test for nonparamet- 2003; Pardo et al, 2004).
ric data both for the comparison between patients and controls In the literature, there are conflicting data regarding
and within each group. The quantitative variables were adiponectin and sex hormone influence (Page et al,
expressed as means 6 SEM. 2005; Seftel et al, 2005; Laughlin et al, 2006; Laughlin et
Resmini et al N Leptin, Ghrelin, and Adiponectin in Transsexuals 583
Figure. Hormonal parameters in the 4 groups: (A) insulin, mUI/mL; (B) HOMA; (C) ghrelin, pg/mL; (D) adiponectin, mg/mL, and (E) leptin, mg/L.
The 4 groups were Males (n 5 15), Females (n 5 14), Male-to-Female transsexuals (M-to-F, n 5 15), and Female-to-Male transsexuals (F-to-
M, n 5 11). *P , .05, **P , .001.
584 Journal of Andrology N September ÙOctober 2008
al, 2007). However, males seem to have lower adipo- inversely related (Panidis et al, 2005). Therefore, we
nectin levels than females, and this androgen-induced expected F-to-M to display lower levels of ghrelin than
adiponectin deficiency (hypoadiponectinemia) may con- normal females. However, the high variability in ghrelin
tribute to the higher cardiovascular risk in males. levels in our female control group might account for the
Hypoadiponectinemia is an independent risk factor for lack of a significant difference between the 2 popula-
endothelial dysfunction, hypertension, coronary heart tions in this study. In fact, if we consider the median in
disease, myocardial infarction, and other cardiovascular Figure 1C (the middle line of the boxplot), we could
complications (Giannessi et al, 2007). speculate ghrelin is higher in females compared with
F-to-M transsexuals could have an increase of their both F-to-M transsexuals and males. Another potential
cardiovascular risk in terms of changes in body explanation might be the relative short time of exposure
composition (Elbers et al, 2003). Moreover hyperan- to androgens of F-to-M transsexuals. However, the data
drogenism, usually resulting from PCOS, is associated on sexual dimorphism of ghrelin are scant, and further
with an unfavorable cardiovascular risk (Gooren et al, studies are warranted to clarify this aspect.
2008). Association of hypoadiponectinemia with meta- In conclusion, our data confirm the sexual dimor-
bolic syndrome in patients with PCOS is reported, and phism in serum leptin levels in normal subjects and show
adiponectin as an endogenous biologically relevant an increase in levels in M-to-F transsexuals. The lower
modulator of vascular remodeling may have a role in adiponectin levels in females treated with androgens
the development of metabolic syndrome in PCOS confirm the literature data that androgens decrease
patients (Gulcelik et al, 2008). plasma adiponectin levels and suggest that F-to-M
The evidence of significantly lower adiponectin levels transsexual subjects could have a higher cardiovascular
in F-to-M transsexuals in comparison with M-to-F risk factor due to the lower adiponectin levels. Ghrelin
patients confirms the data from the literature showing does not display sexual differences and it seems not to be
that androgens decrease plasma adiponectin levels. influenced by exogenous sex hormone administration.
Indeed, F-to-M transsexuals have lower adiponectin However, further studies are needed to shed light on
levels compared with males. Subjects with low adipo- how sex steroids may regulate these hormones.
nectin levels are considered at high cardiovascular risk
because adiponectin plays a role in the pathogenesis of
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