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Adipose Tissue Intracrinology: Potential Importance of Local Androgen/Estrogen Metabolism in the Regulation of Adiposity

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The present article summarizes some of the studies available on steroid hormone conversion through the specific expression of steroidogenic enzymes in adipose tissue (adipose tissue intracrinology) and discusses the potential impact of local adipose tissue steroid metabolism on the regulation of adipocyte function and other metabolic parameters. Several studies have demonstrated significant steroid hormone uptake and conversion by adipose tissues from various body sites and in various cell fractions. Activities and/or mRNAs of aromatase, 3beta-hydroxysteroid dehydrogenase (HSD), 3alpha-HSD, 11beta-HSD, 17beta-HSD, 7alpha-hydroxylase, 17alpha-hydroxylase, 5alpha-reductase and UDP-glucuronosyltransferase 2B15 have been detected in adipose tissue or adipose cells. These studies have demonstrated potentially important roles for these enzymes in obesity, central fat accumulation, and the metabolic syndrome. Future studies on adipose tissue intracrinology will contribute further to our understanding of steroid action in adipocytes.
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Introduction
Body fat distribution shows important sex differences. Men are
usually characterized by the android type of obesity with accu-
mulation of fat in the abdominal region, whereas females display
the gynoid type of obesity with a greater proportion of their body
fat in the gluteal and femoral regions. Excessive accumulation of
adipose tissue within the abdominal cavity (visceral or intra-ab-
dominal obesity) has been demonstrated as a strong correlate of
obesity-related metabolic alterations that are known to increase
the risk of cardiovascular disease [1,2]. Accordingly, men are
characterized by higher incidences of cardiovascular disease, at
least before the age corresponding to menopause in women
[3, 4]. These differences suggest a close association between sex
steroid hormones, regional fat distribution, and concomitant al-
terations in risk factors for cardiovascular disease.
Most studies on sex hormones, obesity, and body fat distribution
have focused on plasma levels of testosterone and estradiol [5].
However, steroid metabolism in humans is much more complex
than what can be observed from simple measures of plasma an-
drogen and estrogen levels. Inactive precursor C
19
steroids are
converted into active androgens/estrogens in peripheral target
tissues, a process that depends on the specific expression of ste-
roidogenic enzymes in each of these tissues, thus allowing hu-
mans to regulate locally the amounts of active steroids on a cel-
lular basis. This newly identified mode of hormone synthesis and
action has been termed intracrinology, and adds to the well-
Adipose Tissue Intracrinology: Potential
Importance of Local Androgen/Estrogen
Metabolism in the Regulation of Adiposity
C. BØlanger
1
V. Luu-The
1
P. Dupont
2
A. Tchernof
1, 3
Affiliation
1
Molecular Endocrinology and Oncology Research Center
2
Gynecology Unit
3
Department of Food Sciences and Nutrition, Laval University Hospital Research Center
(CHUL Research Center) and Laval University, Quebec, Canada
Correspondence
A. Tchernof, Ph.D.´ Molecular Endocrinology and Oncology Research Center ´
Laval University Hospital Research Center ´ 2705 Laurier blvd. (T3-67) Quebec, Qc ´ Canada G1V 4G2 ´
Phone: + 1 (418) 654-2296 ´ Fax: + 1 (418) 654-2761 ´ E-Mail: andre.tchernof@crchul.ulaval.ca
Received 7 October 2002 ´ Accepted after revision 15 November 2002
Bibliography
Horm Metab Res 2002; 34: 737±745 Georg Thieme Verlag Stuttgart ´ New York ´ ISSN 0018-5043
Abstract
The present article summarizes some of the studies available on
steroid hormone conversion through the specific expression of
steroidogenic enzymes in adipose tissue (adipose tissue intracri-
nology) and discusses the potential impact of local adipose tissue
steroid metabolism on the regulation of adipocyte function and
other metabolic parameters. Several studies have demonstrated
significant steroid hormone uptake and conversion by adipose
tissues from various body sites and in various cell fractions. Ac-
tivities and/or mRNAs of aromatase, 3b-hydroxysteroid dehydro-
genase (HSD), 3a-HSD, 11b-HSD, 17b-HSD, 7a-hydroxylase,
17a-hydroxylase, 5a-reductase and UDP-glucuronosyltrans-
ferase 2B15 have been detected in adipose tissue or adipose cells.
These studies have demonstrated potentially important roles for
these enzymes in obesity, central fat accumulation, and the me-
tabolic syndrome. Future studies on adipose tissue intracrinolo-
gy will contribute further to our understanding of steroid action
in adipocytes.
Key words
Androgens ´ Estrogens ´ Adipose Tissue ´ Body Fat Distribution ´
Steroidogenic Enzymes
Review
737
known endocrine and paracrine/autocrine modes of hormone
action [6]. Although the absolute amount of extragonadal ste-
roids synthesized through this mode of action is small, local tis-
sue concentrations achieved are thought to be high, exerting sig-
nificant local biological influence [7].
Adipose tissue has been shown to express several steroidogenic
enzymes that enable this tissue to act as a steroid-metabolizing
organ. The modulation of active steroid levels in this tissue
through the activity of steroid-converting enzymes (adipose tis-
sue intracrinology) may contribute to regulate adipocyte metab-
olism at the local level [8]. On the other hand, given the large in-
terindividual variations in body composition, peripheral steroid
metabolism may be altered in the presence of excessive adipose
tissue accumulations. The present review article summarizes
some of the studies available on adipose tissue intracrinology,
and discusses the potential impact of local adipose tissue steroid
metabolism on the regulation of adipocyte function and other
metabolic parameters.
Steroid Reservoir
Following a first report by Twombly et al. [9] in 1967 demon-
strating the presence of estrogens in adipose tissue, studies per-
formed in the early to late seventies [10± 14] showed that ste-
roids are taken up and converted by adipose tissue. Initial studies
[10± 12] observed aromatization of androstenedione to estrone.
Studies using labeled dehydroepiandrosterone injections dem-
onstrated that this steroid was excreted in the urine at slower
rates in obese individuals compared to lean subjects, suggesting
greater distribution volume in obese subjects [13]. These studies
were supported by direct detection of dehydroepiandrosterone
in adipose tissue samples [14]. Around the same time, other in-
vestigators were confirming adipose tissue uptake and conver-
sion of androgens and estrogens both in vitro and in vivo [15 ±17].
Adipose tissue steroid levels have been examined in a relatively
small number of studies [14,18± 21]. The studies by Deslypere et
al. [18] and FehØr et al. [19] were the first detailed analyses to in-
clude several steroids and adipose tissues originating from var-
ious sites. In the study by Deslypere et al. [18], testosterone,
DHEA-S, DHEA, androstenedione, androstenediol, estrone and
estradiol were detected in adipose tissue. The study by FehØr
also detected cortisol, progesterone, and 17-hydroxyprogester-
one [19]. Both studies found a positive tissue/plasma gradient.
The total steroid content of adipose tissue (estimated with a
mean body fat mass of 20 kg) was 40 ± 400 times greater than to-
tal plasma content (assuming a 3 l plasma volume) in one study
[18]. The estimated size of the tissue steroid pool in the other
study was 2 to 87-fold higher than that of plasma [19]. A positive
gradient was also demonstrated for most steroids examined in a
more recent study [20].
Although large interindividual variations seem to exist in adi-
pose tissue steroid levels [14,18± 20], the question of whether re-
gional differences can be detected within the same patient is less
clear. The study by Deslypere detected only minor differences for
most steroids examined [18]. However, in the recent study by
Szymczak et al. [20], statistically significant differences were
noted between breast adipose tissue content and abdominal adi-
pose tissue content in estradiol, estrone sulfate, estradiol sulfate
and androstenediol. The fact that the differences were most ap-
parent with steroid sulfates is consistent with previous studies,
in which regional differences in DHEA-S were noted; this may
suggest depot-specific steroid converting activities. On the other
hand, several correlations were noted between adipose tissue
levels of the various steroids examined in all studies, and steroids
that were present in higher concentrations in the plasma were
also more concentrated in adipose tissue [20].
Measurements of arteriovenous concentration differences also
provided information on the determinants of steroid uptake by
adipose tissue [22]. These studies are based on a cannulation
technique allowing measurement of arteriovenous differences
across human adipose tissues in vivo. Of interest, the plasma
steroid concentration achieved during the test was a strong de-
terminant of the arteriovenous difference across adipose tissue
[22]. While the handling of androstenedione by adipose tissue
was highly variable in both men and women, testosterone was
consistently taken up by adipose tissue in men but consistently
released in women. Both men and women released estradiol. As-
suming all adipose tissue depots to be equally active, these in-
vestigators estimated that adipose tissue steroid conversion
could account for approximately a third of peripheral androgen
production, and suggested that the importance of this route
would become proportionately greater in obesity [22].
In a study performed in rats, Borg et al. [21] recently demonstrat-
ed that highly lipophilic steroid fatty acid esters could be detect-
ed in adipose tissue of male and female rats. In male rats, castra-
tion resulted in the disappearance of testosterone from fat after 6
hours. However, testosterone fatty acid ester levels fell only after
48 h, and were still detected 10 days after castration. The authors
suggested that these long-lived testosterone esters might repre-
sent a testosterone reservoir in adipose tissue [21]. Steroid esters
have been previously detected in humans [23 ± 25], and could
play a similar role. However, more studies are needed to eluci-
date this possibility, since human adipose tissue steroid-ester
content has not yet been examined.
Large inter-individual variations can be observed in body compo-
sition, and more specifically, in the size of the adipose organ. To
illustrate this variability, Fig. 1 shows percentage fat-free mass
and percentage fat mass values in a sample of women according
to BMI values (Fig.1). The smallest fat mass value observed was
6 kg, which corresponded to 13% fat, and the largest fat mass val-
ue observed was 54 kg, which corresponded to 54 % fat. The re-
markable inter-individual differences that can be observed in
the size of the adipose organ (up to around 10-fold differences
in our sample) as well as its rather large size compared to other
peripheral conversion sites suggests a highly variable, but poten-
tially important influence on steroid metabolism.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
738
Steroidogenic Enzymes
As shown in the previous section, adipose tissue steroid conver-
sion is now a well-accepted phenomenon. Steroidogenic en-
zymes for which mRNA, protein, or activity have been detected
in adipose tissues from various origins or in different adipose tis-
sue cell fractions using various experimental approaches are list-
ed in Table 1. In our survey of the literature, we have identified 13
steroidogenic enzyme types in adipose tissue or adipose tissue-
derived cell fractions (Table 1, Fig. 2). Several groups have de-
scribed the aromatization of androstenedione to estrone and of
testosterone to estradiol very well. Aromatase activity and
mRNA has been detected in adipose tissue from several adipose
tissue depots and cultured stromal cells [18, 26 ± 35]. Important
regional differences in aromatase expression have been ob-
served, with the highest values in adipose tissue from the thighs
and buttocks compared to abdominal and breast adipose tissue
[7]. Moreover, consistent with the increase in fractional conver-
sion rates for androstenedione to estrone observed with aging,
adipose tissue aromatase expression increases markedly with
aging (reviewed in [7]). Experiments performed on adipose tis-
sue cell fractions demonstrated that virtually all the activity ob-
served in whole tissue samples could be detected in isolated
stromal cells, while aromatization was undetectable in mature
adipocytes [31].
Estrone-to-estradiol as well as androstenedione-to-testosterone
conversion (17b-HSD activity) has been shown to occur in hu-
man adipose tissue [18,36]. Type 1, 2, 3 and 5 17b-HSD mRNAs
were all detected in both intra-abdominal and subcutaneous adi-
pose tissues [8, 35,37, 38]. However, mRNA for type 1 17b-HSD
appeared to be incompletely spliced and most likely generates
an inactive protein [8]. Type 2 and 3 enzymes were expressed in
both omental and subcutaneous abdominal adipose tissues [8].
More recently, we found that omental and subcutaneous adipose
tissues also express type 5 17b-HSD (Tchernof and Luu-The, un-
published observation). Additional experiments are currently
underway to determine the physiological importance of this en-
zyme in adipose tissue.
Fig. 2 Schematic representation of steroid conversions and steroidogenic enzymes present in adipose tissue. Sources of steroid precursors in
plasma are indicated on the left. Active steroids at the receptor level are boxed. Glucuronide conjugates potentially produced by adipose tissue
are indicated on the right (±G).
Fig. 1 Percent fat mass and fat-free mass values in a sample of lean,
overweight, and obese women illustrating the large inter-individual
variations in adipose tissue accumulation. The smallest fat mass ob-
served was 6 kg and the largest was 54 kg adipose tissue, which corre-
sponds to a ~ 10-fold difference in the mass of the adipose organ.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
739
Another steroidogenic enzyme expressed in adipose tissue, 11b-
HSD type 1, has recently attracted much attention [39± 41]. Ex-
pression and activity of type 1 11b-hydroxysteroid dehydroge-
nase was demonstrated in stromal cells from breast, omental,
and subcutaneous adipose tissue [40, 42]. Contrary to the classi-
cal view that adipose tissue contributes to the deactivation of
cortisol by transforming it to cortisone [43], studies have found
that the predominant activity in omental fat, and to a lesser ex-
tent abdominal subcutaneous fat, was the reduction of inactive
cortisone to active cortisol [40, 44]. As opposed to aromatase
and 17b-HSD expression, which was mostly found in preadipo-
cytes, the expression of type 1 11b-HSD has been shown to be
activated upon adipocyte differentiation, which is thought to
promote lipogenesis [45]. The site-specific regulation of this ac-
tivation may represent an important etiological factor underly-
ing visceral obesity development [45].
Several other enzymes have been identified in human adipose
tissue (Table 1, Fig. 2). Of note, 5a-reductase activity has been de-
tected, which emphasizes the ability of this tissue to generate di-
hydrotestosterone, the most active androgen, from testosterone
[46]. Abdominal subcutaneous adipose tissue also expresses
P450 C17 mRNA (17a-hydroxylase), which is responsible for the
formation of 17-hydroxyprogesterone, adding another possible
pathway for the synthesis of active androgens/estrogens in this
tissue [47].
On the other hand, enzymes that inactivate androgens have also
been detected in adipose tissue. Messenger RNA or activity of
these enzymes, type 3 3a-HSD, 17a-hydroxylase, and UDP-glu-
curonosyltransferase (UGT) 2B15 have been detected in adipose
tissue and stromal cells, and may be responsible for modulating
exposure of adipose cells to active steroids. In support of this no-
tion, we recently found that the glucuronidated form of 5a-an-
drostane-3a,17b-diol (the major product of 3a-HSD and
UGT2B15), was elevated in plasma of overweight men with vis-
ceral obesity [48]. These results suggested that androgen metab-
olism was increased in men with abdominal obesity. Further
support was provided by a study of twins who were submitted
to overfeeding [49]. We induced a 7 % increase in percent fat
that was associated with a 24 cm
2
increase in visceral adipose
tissue cross-sectional area. These changes led to significant in-
creases in plasma levels of androstane-3a,17b-diol glucuronide
[49]. Changes in adipose tissue distribution indices were signifi-
cantly correlated with changes in plasma concentrations of this
androgen metabolite, suggesting that body fat gain is associated
with alterations in local androgen inactivation [49]. A second
glucuronosyltransferase (UGT2B11) was also detected in adipose
tissue [50]. However, no specific substrate has yet been attribut-
ed to this isoform.
Potential Importance of Local Adipose Tissue Steroid
Metabolism in the Regulation of Adiposity
Androgen concentrations are around 5 ±10 times higher in males
than in females [51]. This difference in steroid profile correlates
with the presence of the android pattern of fat distribution in
males. In support of this observation, long-term, high-dose an-
drogen treatment of female-to-male transsexuals leads to a
change in the pattern of fat distribution, with the predominance
of abdominal fat [52]. Within the male physiological range, how-
ever, higher testosterone levels appear to be beneficial to men
[53]. Hence, overall male obesity and overweight have generally
been associated with reduced endogenous plasma testosterone
levels and increased estrogen concentrations [54 ± 56]. Low en-
dogenous testosterone levels also characterize men with visceral
obesity [57,58]. In a previous study [56], we confirmed findings
by other groups [57, 58] showing that abdominal obesity is asso-
ciated with reduced plasma testosterone concentrations. In addi-
tion, adrenal C
19
steroid concentrations (androstenedione, an-
drostenediol, and dehydroepiandrosterone) were also reduced
in abdominal obese men when compared to lean controls [56].
Thus, obesity and excess abdominal adipose tissue accumulation
are not only associated with reductions in plasma levels of gona-
dal steroids, but also with low adrenal C
19
steroid concentrations
in men.
Mechanisms responsible for the complex pattern of associations
among androgens, obesity, and body fat distribution are still un-
clear. Björntorp and colleagues (reviewed in [59]) have suggested
that visceral obesity may arise from an activation of the cortico-
trophin-releasing factor-adrenocorticotrophin-cortisol axis re-
sulting from a variety of causes, including nutritional factors, po-
tential stressors in the psychosocial and socioeconomic environ-
ment, alcohol, smoking, traits of depression, anxiety, and genetic
susceptibility. Activation of the axis would be partly responsible
for alterations in glucose transport, insulin sensitivity and adi-
pose tissue metabolism, which could contribute to an inhibition
of gonadotrophin secretion, and may explain the low androgen
levels found in the plasma of visceral obese men [1,60, 61]. How-
ever, this hypothesis remains to be confirmed. The alternative
view suggests that reduced androgens in male obesity are not a
primary etiologic factor, but the result of an increased clearance
through accelerated conversion in an enlarged adipose tissue or-
gan.
Irrespective of the precise mechanism responsible for reduced
androgen levels in the plasma of abdominal obese men, evidence
is available to suggest that, on a local level, exposure of adipose
cells to less active androgen molecules directly impact on adi-
posity regulation and abdominal adipose cell metabolism. Spe-
cifically, androgens have been shown to enhance the lipolytic ca-
pacity of cultured male rat adipose precursor cells by increasing
the number of b-adrenoceptors and the activity of adenylate cy-
clase [62]. An increased fatty acid turnover has also been ob-
served in human males treated with testosterone [63,64], as
these studies demonstrated that testosterone treatment inhib-
ited the activity of adipose tissue lipoprotein lipase, an important
regulator of lipid uptake by the adipocyte [63, 64]. Evidence of a
direct action by androgens in adipose tissue also comes from
studies that have demonstrated the presence of androgen recep-
tors [65] and androgen binding [66,67] in both human and ro-
dent adipose tissue. Taken together, the available data suggest a
close association between androgens on the one hand and body
fat accumulation and distribution on the other. At the adipocyte
level, androgens directly modulate lipid mobilization and lipid
uptake, presumably by specifically binding to androgen recep-
tors expressed in adipose tissue.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
740
Table 1 Steroidogenic enzymes in human adipose tissue
Enzyme Type Biological Material Studied mRNA Protein Activity Study
Aromatase Abdominal subcutaneous tissue + nd nd McTernan et al., 2000 [26]
Abdominal subcutaneous
and visceral adipose tissue
nd nd (D
4
dione ® E
1
) Deslypere et al., 1985 [18]
Breast adipose tissue + nd nd Price et al., 1992 [27]
Thighs/buttocks/abdomen
subcutaneous adipose tissue
+ nd nd Bulun et al., 1994 [28]
Stromal cells (subcutaneous) nd nd (C19
® C18) McTernan et al., 2000 [26]
nd nd (T
® E
2
) Schmidt et al., 1994 [29],
Schmidt et al., 1998 [30]
+nd(D
4
dione ® E
1
) Simpson et al., 1989 [31],
Zhao et al., 1997 [32]
+nd(T
® E
2
) Schmidt et al., 1998 [30]
nd nd (D
4
dione ® E
1
) Killinger et al., 1990 [33]
Stromal cells (breast) nd nd (D
4
dione ® E
1
) Perel et al., 1986 [34]
Stromal cells (subcutaneous
and visceral)
+nd(D
4
dione ® E
1
) (c) Corbould et al., 2002 [35]
3b-HSD Stromal cells (breast) nd nd (DHEA
® D
4
dione) Killinger et al., 1995 [86]
3a-HSD 3 Abdominal subcutaneous
and visceral adipose tissue
+ nd nd Tchernof and Luu-The
[unpublished observation]
3 Stromal cells (subcutaneous
and visceral)
nd nd (DHT
® 3a-diol) Blouin, Tchernof and Luu-The [unpub-
lished observation], Joyner et al. [68]
11b-HSD 1 Abdominal subcutaneous tissue nd nd (F
® E) Rask et al., 2001 [87]
1 Stromal cells (subcutaneous
and visceral)
+nd(E
® F) Tomlinson et al., 2000 [88]
1 Stromal cells and mature adipocytes nd nd (E
® F) Ricketts et al., 1998 [89]
1 +nd(E« F) Bujalska et al., 2002 [45]
1 Stromal cells nd nd (E
® F) Moore et al., 1999 [90]
1 +nd(E
® F) Bujalska et al., 1999 [91],
Tomlinson et al., 2001 [88]
17b-HSD Abdominal subcutaneous tissue nd nd (E
1
® E
2
) Folkerd et al., 1982 [36]
Abdominal subcutaneous
and visceral adipose tissue
nd nd (E
2
® E
1
) Deslypere et al., 1985 [18]
Breast adipose tissue nd + (E
1
® E
2
) Tait et al., 1989 [92],
Mann et al., 1991[93]
+nd(E
1
« E
2
); (T « D
4
dione) Labrie et al., 1997 [94]
Stromal cells (breast) nd nd (D
4
dione ® T) Perel et al., 1986 [34]
nd nd (DHEA
® D
5
diol) Khalil et al., 1993 [95]
1 Abdominal subcutaneous
and visceral tissues
+ (d) nd nd Corbould et al., 1998 [8]
2 Abdominal subcutaneous
and visceral tissues
+ nd nd Corbould et al., 1998 [8]
2 Abdominal subcutaneous tissue + nd nd Luu-The et al., 1990 [37],
Labrie et al., 1991 [38]
3 Abdominal subcutaneous
and visceral tissues
+ nd nd Corbould et al., 1998 [8]
3 Stromal cells/preadipocytes
(subcutaneous and visceral)
+nd(D
4
dione ® T) Corbould et al., 2002 [35]
5 Abdominal subcutaneous
and visceral tissues
+ nd nd Tchernof and Luu-The
[unpublished observation]
7a-hydroxy-
lase
Stromal cells (breast) nd nd (DHEA
® 7a-OHDHEA) Khalil et al., 1993 [95], Khalil et al.,
1994 [96], Killinger et al., 1995 [86]
17a-hydroxy-
lase
Abdominal subcutaneous tissue + nd (P
® 17a-OHP) Puche et al., 2002 [47]
5a-reductase Adipose tissue (a) nd nd (T
® DHT) Longcope et al., 1985 [46]
Continued
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
741
Thus, available data on androgens and body fat distribution ap-
pear to be contradictory. On the one hand, abdominal obesity is
associated with reduced testosterone in plasma; on the other,
androgens directly promote lipid mobilization and inhibit lipid
uptake in adipocytes. Adipose tissue steroid conversion may re-
present an interesting hypothesis to reconciling the available
data. Indeed, an increased elimination of plasma androgens
through accelerated conversion to non-androgenic steroids in
adipose tissue is consistent with a lower exposure of adipocytes
to active androgens at the local level. Accordingly, a recent study
by Joyner et al. [68] indicated that dihydrotestosterone metab-
olism to 3a-diol was significant in preadipocytes, and that this
phenomenon may have led to slight decreases in DHT binding
to its receptor.
In female adipose tissue, estrogens have been shown to exert ac-
tions that are partly similar to those of androgens in males (re-
viewed in [69±71]). Specifically, estradiol may directly inhibit
lipid uptake through inhibition of lipoprotein lipase, and pro-
mote lipid mobilization through stimulation of lipolysis [69]. Ad-
ditional evidence for a role of estrogens in the regulation of adi-
pose tissue accretion and distribution comes from studies that
have demonstrated the presence of both estrogen receptor iso-
forms in this tissue [72± 78]. Human and animal studies have re-
ported evidence for regional differences in adipose tissue estro-
gen receptor levels and regulation [74,76]. Taken together, these
data suggest that adipose tissue is responsive to estrogens, and
that these effects may be depot-specific. Consequently, an in-
creased intracrine conversion of steroid precursors to estradiol
in adipose tissue may contribute to the local regulation of adi-
pose tissue store size and distribution in women. A recent study
by Corbould et al. [35] examined abdominal subcutaneous and
intra-abdominal adipose tissue samples in women. The authors
found a positive correlation between ratio of type 3 17b-HSD to
aromatase in intra-abdominal adipose tissue on the one hand
and waist circumference and BMI on the other, suggesting that
female adipose tissue was substantially androgenic, which in-
creased with obesity or central obesity [35]. Additional indirect
evidence supporting the hypothesis of an important role for adi-
pose tissue-produced estrogens in the regulation of adipocyte
metabolism and obesity-related conditions also comes from
studies on breast adipose tissue aromatase and breast cancer,
which constitute a well-accepted connection [7, 31]. More studies
are needed to firmly establish the physiological relevance of the
intracrine mode of hormonal action in the regulation of adiposity.
The generation of active cortisol through expression of type 1
11b-HSD in abdominal adipose tissue, which has been shown to
increase exposure of omental adipocytes to cortisol, appears to
be of particular importance in the pathogenesis of abdominal
obesity and related metabolic complications. Recent data have
indicated that the dehydrogenase activity of type 1 11b-HSD
was predominant in preadipocytes, and that there was a switch
to oxoreductase activity upon initiation of cell differentiation
[45]. This study suggested that the switch to cortisol production
by type 1 11b-HSD in differentiating adipocytes likely promotes
lipogenesis, which led the authors to propose that the set point
of type 111b-HSD oxoreductase activity may represent an impor-
tant mechanism underlying visceral obesity. Rask et al. per-
formed a study on peripheral cortisol metabolism and the regu-
lation of the hypothalamic-pituitary-adrenal axis [79]. They
found that obese women were characterized not only by in-
creased cortisol activation by subcutaneous adipose tissue 11b-
HSD1 activity, but also by a decreased hepatic activation of corti-
sol from cortisone and increased inactivation of cortisol by A-
ring reductases. This led to increased urine levels of cortisol me-
tabolites such as 5a- and 5b-tetrahydrocortisol. Minimal com-
pensatory activations of the hypothalamic-pituitary-adrenal
axis were noted in obese subjects, and were found to be insuffi-
cient to account for the increased plasma cortisol levels observed
in this condition. These results demonstrated that adipose tissue
11b-HSD1 activity might represent a key contributor to the circu-
lating pool of cortisol [79]. Another study demonstrated that
transgenic mice selectively expressing 11b-HSD type 1 in adipose
tissue develop abdominal obesity, a phenomenon that is exag-
gerated by a high-fat diet [41]. The investigators suggested that
increased expression of 11b-HSD1 in abdominal adipose tissue
might represent a common molecular etiology for visceral obesi-
ty and the metabolic syndrome [41]. These studies dramatically
emphasize the importance of steroid conversions in adipose tis-
sue. The potential impact of other adipose tissue steroidogenic
enzymes that would decrease or increase the exposure of omen-
tal adipocytes to active androgens/estrogens in a manner similar
to 11b-HSD1/cortisol remains to be studied.
Table 1 Continued
Enzyme Type Biological Material Studied mRNA Protein Activity Study
Stromal cells (breast) nd nd (D
4
dione ® D
5
dione) Perel et al., 1986 [34]
Stromal cells nd nd (D
4
dione ® D
5
dione) Killinger et al., 1990 [33]
UGT2B11 Adipose tissue (b) + nd nd Beaulieu et al., 1998 [50]
UGT2B15 Adipose tissue (b) + nd nd LØvesque et al., 1997 [97]
Abdominal subcutaneous
and visceral tissues
+ nd nd Tchernof et al., 1999 [98]
nd: not determined; (a): Arterial venous balance; (b): Not possible to determine biopsy site; (c): low activity detected; (d): incompletely spliced mRNA detected,
most likely leads to inactive protein; UGT: UDP-glucuronosyltransferase; D
4
dione: androstenedione; E
1
: estrone; C
19
: androgens; C
18
: estrogens; T: testosterone;
E
2
: estradiol; DHEA: dehydroepiandrosterone; DHT: dihydrotestosterone; 3a-diol: androstanediol; E: cortisone; F: cortisol; D
5
diol: androst-5-ene-3b,17b-diol;
7a-OHDHEA: 7a-hydroxydehydroepiandrosterone; P: progesterone; 17a-OHP: 17a-hydroxyprogesterone; D
5
dione: androstanedione.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
742
Conclusion
Over the last decade, the incidence of obesity has steadily in-
creased in North America and Europe [80 ± 83]. Recent epidemio-
logical studies showing parallel increases in the incidence of
both obesity and type 2 diabetes have emphasized more than
ever the need for concerted efforts to understand, prevent and
treat these conditions [84,85]. The close relationship between
obesity and plasma sex hormones is well established. However,
steroid metabolism in humans is much more complex than
what can be observed from simple measures of plasma androgen
and estrogen levels. The adipose organ acts as a steroid reservoir
and site of conversion. Local androgen/estrogen synthesis in adi-
pose tissue may account for an important part in steroid action,
and presumably adiposity regulation. Several steroid-converting
activities and steroidogenic enzymes have been detected in adi-
pose tissues, and recent studies have demonstrated potentially
important roles for these enzymes in the metabolic syndrome.
Future studies on adipose tissue intracrinology will contribute
further to our understanding of steroid action in adipocytes.
Acknowledgments
AndrØ Tchernof is the recipient of a Fonds de la Recherche en
SantØ du QuØbec Scholarship. This work was supported by the
Canadian Diabetes Association and the Canadian Institute of
Health Research. Chantal BØlanger is the recipient of a summer
studentship from Human Resources Development Canada.
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... This could be attributed to obesity, which is connected with sex hormone imbalance and low level of sex hormone-binding globulin (SHBG). The exact cause of infertility among the obese women appears to be the absence of long anovulation due to hyperandrogenism caused by obesity [47] [48]. ...
... The study observed that obese women with primary infertility and secondary infertility suffer more from hyperestrogenism 202 (68.01%) and 154 (70.73%) than any other gonadal disorders. The high predominance of hyperestrogenism in obese infertile women could be attributed to the fact that obesity is linked with high estrogen levels, as would be expected from androgen aromatization in adipocytes [48]. It may also be due to a sex hormone imbalance and low levels of sex hormone-binding globulin (SHBG), which can increase the target tissue's exposure, to free estrogen [49]. ...
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Full-text available
Background: Infertility is well-known global health problem that has significant impacts on an individual, families and communities. Many modifiable lifestyle risk factors increase the risk of women to several reproductive disorders. Aim: This study established the relationship between obesity and Hypothalamic-Pituitary-Ovarian (HPO) axis hormones in infertile women in the Niger Delta Region, Nigeria. Methodology: Six hundred and twenty-six (626) women aged 18 - 40 years comprising of 513 obese infertile women and 113 non obese women who served as control were recruited for the study. Anthropometric measurements were taken and Body Mass Index was calculated. A non-fasting venous blood sample was collected from the women and analyzed for serum Estrogen, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Progesterone, Inhibin B, and Prolactin using Enzyme linked immunosorbent assay method. Results: In the present study, the Body Mass Index of women with primary (1˚) infertility is significantly (p < 0.05) higher than secondary (2˚) infertility women. Whereas, women with 2˚ infertility were older and have a higher height than women with 1˚ infertility. The result revealed that serum estrogen, luteinizing hormone, follicle stimulating hormone and prolactin levels were significantly (p < 0.05) higher in the obese infertile women, while inhibin B and progesterone levels were significantly (p< 0.05) reduced in the obese infertile women compared to the control subjects. However, women with 1˚ infertility have a significantly higher LH and FSH levels than the 2˚ infertility women. Furthermore, the study revealed that hyperestrogenism is the most prevalent gonadal disorder in women with primary infertility and secondary infertility. The BMI of infertile women suffering Hyperestrogenism is significantly higher than any other female gonadal disorder. The result also showed that there is statistically significant positive correlation between BMI and Hypogonadism, Hypogonadotropic and Amenorrhoea in obese infertility women. While, no significant correlation between BMI and Hypergonadism and Hypergonadotropic was observed. Furthermore, there was a positive correlation between BMI and Hypothalamus-Pituitary Ovarian hormones, as BMI showed a positive correlation with LH, FSH, Estrogen, progesterone, and prolactin in women with primary and secondary infertility, while Inhibin B showed a negative correlation with BMI. Conclusion: There is a relationship between BMI and Hypothalamus-Pituitary Ovarian hormones, signifying that obesity could affect female reproduction and directly impact ovarian function. Therefore, body weight maintenance should be considered as a first line of management of Hypothalamus-Pituitary Ovarian hormonal related infertility.
... Estrogen deficiency promotes metabolic dysfunction, which lately predisposes to obesity, metabolic syndrome, and type 2 diabetes. On the contrary, obesity is associated with elevated estrogen levels due to increased production in adipocytes (44), giving rise to risk factors for breast cancer development and cardiovascular disease. Figure 2 explains correlation of hormonal imbalance with obesity. ...
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Obezite, dünya çapında yaygın olan en önemli yaşam tarzı bozukluklarından biridir. Artan obezite oranı, tiroid disfonksiyonu, dislipidemi, hormonal dengesizlik vb. hastalıkların ortaya çıkması ile ilişkilidir. Obezite, kalp hastalığı, ateroskleroz, insülin direnci, artrit, kas-iskelet sistemi bozuklukları ve kanser için risk faktörüdür. Bu makale, obezitenin dislipidemi, diyabet, hormonal dengesizlik ve hipotiroidizm ile ilişkisine dair içgörüler sunmaktadır. Leptin, insülin, seks hormonları ve büyüme hormonları iştahı, metabolizmayı ve vücut yağ dağılımını etkilediğinden hormonların aşırı veya yetersiz salınımı obeziteye yol açabilir. Makale, metabolik düzensizliğin obezite ile ilişkisi ve ilgili hastalıkların daha da geliştirilmesi hakkında bir inceleme sunmaktadır. Bu makale aynı zamanda diyet liflerinin ve balık proteininin metabolik değişiklikler, hormonal dengesizlik ve obezite ile ilişkili hiperlipidemi üzerindeki etkilerini de özetlemektedir. Bu makale, obezite ile ilgili bozuklukları yönetmek için yararlı olan lif ve diyet protein tüketimi gibi diyet müdahalesinin rolünü detaylandırdı. Potansiyel nutrasötik ürünler sık besin kaynakları olarak tüketilmektedir. Yine de, kaliteli insan klinik deney verileri eksiktir, bu da nutrasötiklerin güvenliğini ve etkinliğini değerlendirmek için önemli bilimsel çalışmalara ihtiyaç olduğunu gösterir.
... Several biological mechanisms have been hypothesized to explain adiposity-promoting gonadal axis initiation. One of the hypotheses is that increased adiposity could enhance aromatase activity and stimulate the conversion of androgens into estrogen, thereby triggering earlier pubertal onset (53). Similarly, insulin resistance induced by adiposity is linked to a decreased level of sex-hormone-binding globulin, which increases sex steroid bioavailability and precipitates early breast development (54). ...
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Objective An ongoing debate surrounds the relationship between body composition and pubertal timing, in particular for boys. This cross-sectional study aimed to investigate the association of body composition with pubertal timing among children and adolescents. Methods A total of 1,493 boys and 1,261 girls who entered puberty were enrolled in Guangzhou, China. Tanner stages were evaluated by examination of breast development for girls and testicular volume for boys. Fat mass (FM) and fat-free mass (FFM) were determined by bioelectrical impedance analysis. Parameters for body composition were transformed into age-and gender-specific Z -scores. The association of body composition with pubertal timing was examined using multinomial logistic regression with inverse probability weighting (IPW) based on the propensity score. Results For boys, IPW analysis showed Z -scores of body fat percentage (BF%) and FM index (FMI) were negatively associated with early puberty (OR = 0.75, 95% CI = 0.64–0.87; OR = 0.74, 95% CI = 0.63–0.88). As for girls, in contrast to boys, positive associations were seen between BF% and FMI with early puberty (OR = 1.39, 95% CI = 1.19–1.64; OR = 1.59, 95% CI = 1.33–1.90). With respect to appendicular skeletal muscle mass index (ASMI), there was a positive association with early puberty and a negative one with late puberty in boys (OR = 1.26, 95% CI = 1.07–1.49; OR = 0.82, 95% CI = 0.69–0.99). Conclusion There is a positive association of FM with early puberty for girls while negative for boys. FFM yields a positive association with early puberty and a negative one with late puberty in boys, but not in girls. Our findings highlight the gender differences in the connection between body composition and pubertal onset.
... Obesity is a consequence of the increased accumulation of lipids and expansion of AT. As testosterone is a fat-soluble molecule, we can speculate that it is likely to be sequestered into AT depots, leading to reduced circulating levels of this substance in obesity; however, to date, the measurement of steroid concentrations in fat cells and tissue has produced conflicting results [17][18][19]. Indeed, adipocytes from subcutaneous AT (SAT) retrieved from obese men were shown to have higher concentrations of intracellular testosterone as compared with those retrieved from lean men [20]. Despite this greater testosterone accumulation, SAT from obese patients had lower expression of androgenresponsive genes involved in the lipolytic and anti-adipogenic pathways, suggesting the altered function of adipose cells in these individuals. ...
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Obesity is a chronic illness associated with several metabolic derangements and comorbidities (i.e., insulin resistance, leptin resistance, diabetes, etc.) and often leads to impaired testicular function and male subfertility. Several mechanisms may indeed negatively affect the hypothalamic–pituitary–gonadal health, such as higher testosterone conversion to estradiol by aromatase activity in the adipose tissue, increased ROS production, and the release of several endocrine molecules affecting the hypothalamus–pituitary–testis axis by both direct and indirect mechanisms. In addition, androgen deficiency could further accelerate adipose tissue expansion and therefore exacerbate obesity, which in turn enhances hypogonadism, thus inducing a vicious cycle. Based on these considerations, we propose an overview on the relationship of adipose tissue dysfunction and male hypogonadism, highlighting the main biological pathways involved and the current therapeutic options to counteract this condition.
... Par exemple l'aromatase et la 17 ß-HSD sont retrouvées dans le tissus adipeux viscéral (255). L'aromatase qui transforme, dans le TA, la 5-dihydrotestosterone (DHT) en oestrogène pourrait être impliquée dans des désordres biologiques comme le syndrome métabolique et l'obésité(256)(257)(258). Si en situation physiologique, les estrogènes sont plutôt antiadipogénique, leurs effets sont néfastes lorsque la sécrétion n'est plus régulée. ...
Thesis
Des études récentes ont montré que l'un des composants majeurs du microenvironnement de la prostate, le tissu adipeux périprostatique (TAPP) participe à la progression du cancer de la prostate (CaP). Dans ce travail nous avons montré que ce tissu était dans un état hypoxique associé à une réponse inflammatoire et une augmentation des fibres de collagènes. Ensuite, nous avons observé une association entre accumulation excessive de TAPP et l'agressivité du CaP. Sur le plan biologique, nos résultats préliminaires montrent qu'un remodelage extensif de la matrice extracellulaire (MEC) dans les TAPP abondants permet leur expansion et contribue à la génération de fragments bioactifs de la MEC impliqués dans la progression tumorale. En conclusion, ces résultats ouvrent de nouvelles pistes sur les mécanismes permettant au TAPP d'être un acteur dans la progression du CaP et souligne le rôle majeur de la MEC dans le contrôle de son expansion mais également dans la progression du CaP.
... Preliminary epidemiological evidence shows that compared to being normal weight, maternal obesity is associated with lower placental estradiol synthesis (Gomes et al., 2014) and higher blood testosterone levels in women carrying males (Maliqueo et al., 2017). These observations are likely due to the hormonal activity of adipose tissue, as it is a major site of estrogen and androgen metabolism (Belanger et al., 2002;Kershaw and Flier, 2004). Given the complex interplay between hormones and adipose tissue, and the increased prevalence of overweight/obesity among reproductive-age women, our primary objective was to evaluate associations of pre-and early-pregnancy maternal anthropometric measures with AGD and 2:4D. ...
Article
STUDY QUESTION Are maternal anthropometrics associated with anogenital distance (AGD) and 2:4 digit ratio (2:4D) in newborns? SUMMARY ANSWER Select maternal anthropometrics indicative of obesity or increased adiposity are associated with elongated AGD in daughters. WHAT IS KNOWN ALREADY Excessive maternal weight or adiposity before or in early pregnancy may impact child reproductive, and other hormonally mediated, development. AGD and 2:4D are proposed markers of in utero reproductive development. STUDY DESIGN, SIZE, DURATION This study includes 450 mother/newborn dyads participating in the Illinois Kids Development Study (I-KIDS), a prospective pregnancy cohort from Champaign-Urbana, IL, USA. Participants included in the current study enrolled between 2013 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Most mothers in this study were college-educated (82%) and non-Hispanic White (80%), and 55% were under- or normal weight before pregnancy. Pregnant women aged 18–40 years reported pre-pregnancy weight and height to calculate pre-pregnancy BMI. At 8–15 weeks gestation, we measured waist and hip circumference, and evaluated weight, % body fat, visceral fat level, % muscle and BMI using bioelectrical impedance analysis. Within 24 h of birth, we measured newborn 2nd and 4th left/right digits to calculate the 2:4D. In daughters, we measured AGDAF (anus to fourchette) and AGDAC (anus to clitoris). In sons, we measured AGDAS (anus to scrotum) and AGDAP (anus to base of the penis). MAIN RESULTS AND THE ROLE OF CHANCE Select maternal anthropometrics were positively associated with AGD in newborn daughters, but not sons. For example, AGDAC was 0.73 mm (95% CI: 0.15, 1.32) longer for every interquartile range (IQR) increase in pre-pregnancy BMI and 0.88 mm (95% CI: 0.18, 1.58) longer for every IQR increase in hip circumference, whereas AGDAF was 0.51 mm (95% CI: 0.03, 1.00) and 0.56 mm (95% CI: 0.03, 1.09) longer for every IQR increase in hip and waist circumference, respectively. Quartile analyses generally supported linear associations, but additional strong associations emerged in Q4 (versus Q1) of maternal % body fat and visceral fat levels with AGDAC. In quartile analyses, we observed only a few modest associations of maternal anthropometrics with 2:4D, which differed by hand (left versus right) and newborn sex. Although there is always the possibility of spurious findings, the associations for both measures of female AGD were consistent across multiple maternal anthropometric measures, which strengthens our conclusions. LIMITATIONS, REASONS FOR CAUTION Our study sample was racially and ethnically homogenous, educated and relatively healthy, so our study may not be generalizable to other populations. Additionally, we may not have been powered to identify some sex-specific associations, especially for 2:4D. WIDER IMPLICATIONS OF THE FINDINGS Increased maternal weight and adiposity before and in early pregnancy may lengthen the female AGD, which warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S) This publication was made possible by the National Institute for Environmental Health Sciences (NIH/NIEHS) grants ES024795 and ES022848, the National Institute of Child Health and Human Development grant R03HD100775, the U.S. Environmental Protection Agency grant RD83543401 and National Institute of Health Office of the Director grant OD023272. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the US EPA or NIH. Furthermore, the US EPA does not endorse the purchase of any commercial products or services mentioned in the publication. This project was also supported by the USDA National Institute of Food and Agriculture and Michigan AgBioResearch. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.
... While the least prevalent gonadal disorder was Hypergonadism in subjects with primary infertility (7.07%) and secondary infertility (6.487%). The prevalence of hyperestrogenism in obese women with infertility is due to the fact that obesity is associated with high estrogen levels, as would be expected from androgen aromatization in adipocytes (Belanger et al., 2002). It may also be due to a sex hormone imbalance and low levels of sex hormone-binding globulin (SHBG), which can increase the target tissue's exposure to free estrogen. ...
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Background: Obesity is a medical problem that increases the risk to many reproductive issues in women, and there is a high prevalence of obese women in the population attending the different fertility clinics in the Niger Delta Region of Nigeria. Objective: This cross-sectional study was carried out to assess reproductive hormones in obese infertile women. Methods: A total of 626 women comprising of 513 obese infertile women and 113 not obese women who serve as control were recruited for the study.Anthropometric measurements were taken and Body Mass Index were calculated. A non-fasting venous blood sample was collected from the subjects and analyzed for serum Estrogen, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Progesterone, Inhibin, and Prolactin. Results: The result revealed that obese infertile women with primary and secondary infertility showed a statistically significant (p<0.05) increase in estrogen, LH, FSH, prolactin levels, and decreased progesterone and inhibin levels. However, women with secondary infertility had slightly higher levels of all analyzed hormones than primary infertility women. The study also revealed that hyperestrogenism was more prevalent among the obese women with primary infertility and secondary infertilitycompared with other gonadal disorders, but slightly higher in secondary infertility women. Infertility showed positive correlation with Body Mass Index. LH, FSH, E2, progesterone and prolactin showed a positive correlation withBMI in primary and secondary infertility women, while inhibin showed a negative correlation with Body Mass Index.Conclusion: Therefore, weight loss should be considered as a first line of treatment in obese women with hormonal imbalance.
... We were unable to incorporate oestrogen into this analysis as we were unable to identify reliable genetic instruments for this trait. All three of the molecular mediators highlighted in this analysis, however, are known to influence oestrogen: bioavailable testosterone is aromatized to oestradiol; SHBG binds with high-affinity to both oestradiol and bioavailable testosterone [100][101][102][103][104][105]; and insulin increases androgen and decreases SHBG production [106][107][108][109]. We found the inverse effect of SHBG on endometrial cancer risk was largely attenuated upon adjustment for bioavailable testosterone, suggesting a protective effect of SHBG may be driven via binding of biologically active fractions of circulating testosterone. ...
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Background Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated ( P < 5.0 × 10 ⁻⁸ ) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. Results In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10 ⁻³¹ ), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10 ⁻¹² ), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10 ⁻⁹ ), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10 ⁻⁷ ) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10 ⁻⁴ ) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10 ⁻² ) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10 ⁻³ ), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10 ⁻⁸ ) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10 ⁻² ) in the relationship between BMI and endometrial cancer risk. Conclusions Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.
Article
Even in the 21 st century, female participants continue to be underrepresented in human physiology research. This underrepresentation is attributable in part to the perception that the inclusion of females is more time consuming, less convenient, and more expensive relative to males due to the need to account for the menstrual cycle in cardiovascular study designs. Accounting for menstrual cycle-induced fluctuations in gonadal hormones is important, given established roles in governing vascular function and evidence that failure to consider gonadal hormone fluctuations can result in misinterpretations of biomarkers of cardiovascular disease. Thus, for cardiovascular researchers, the inclusion of females in research studies implies a necessity to predict, quantify, and/or track indices of menstrual cycle-induced changes in hormones. It is here that methodologies are lacking. Gold standard measurement requires venous blood samples, but this technique is invasive and can become both expensive and technically preclusive when serial measurements are required. To this end, saliva-derived measures of gonadal hormones provide a means of simple, non-invasive hormone tracking. To investigate the feasibility of this technique as a means of facilitating research designs that take the menstrual cycle into account, the purpose of this review was to examine literature comparing salivary and blood concentrations of the primary gonadal hormones that fluctuate across the menstrual cycle: estradiol and progesterone. The data indicate that there appear to be valid and promising applications of salivary gonadal hormone monitoring, which may aid in the inclusion of female participants in cardiovascular research studies.
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Bulimia nervosa (BN) is characterized by binge eating, compensatory behavior, over-evaluation of weight and shape, which often co-occur with symptoms of anxiety and depression. Depression is the most common comorbid diagnosis in women with eating disorders. The role of androgens in the pathophysiology of depression has been recognized in recent years. However, the research on psychopathological comorbidity and androgen levels in bulimic disease is sparse. This study aimed to investigate, if there were any correlations between the androgens, testosterone (T), dehydroepiandrosterone sulphate (DHEAS), androstenedione (A4), 5α-dihydrotestosterone, (5α-DHT), and test scores of psychopathological variables, in women with bulimia nervosa (BN), eating disorder not otherwise specified of purging subtype (EDNOS-P) assessed by CPRS, and EDI 2. Women with DSM-IV diagnosis of BN (n = 36), EDNOS-P (n=27), and healthy control subjects (n=58) evaluated for fifteen psychopathological variables, i.a. depressive symptoms, impulsivity, personal traits, as well as serum androgen levels. All women were euthyroid, and polycystic ovarian syndrome (PCOS) diagnosis was excluded. Although androgen levels were almost equal for all three groups, significant correlations between core psychopathological symptoms (9/15) of bulimia nervosa and the most potent endogenous androgen, 5α-DHT, was found only in the EDNOS-P group. The role of 5α-DHT in women is not fully elucidated. Both animal and human studies have shown that the brain is able to locally synthesize steroids de novo and is a target of steroid hormones. Maybe these results can be interpreted in the light of differences in androgen receptor variability, metabolism and origin of T and 5α-DHT.
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Clinical evidence suggests that sex hormones affect adipose tissue metabolism and deposition. To investigate the biosynthesis and possible action of estrogen in adipose tissue, we report the use of competitive, specific polymerase chain reaction amplifications to determine levels of estrogen receptor (ER) messenger RNA (mRNA) and cytochrome P450 aromatase mRNA in adipocytes and adipose stromal cells. This extremely sensitive technique uses coamplification of a homologous animal species complementary RNA to control for differences in amplification efficiencies. The DNA amplification products are identified by Southern hybridization with species-specific radiolabeled oligonucleotide probes. Abdominal adipose tissue obtained from female patients during elective abdominoplasty was separated by collagenase digestion and centrifugation into floating adipocytes and pelleted adipose stromal cells. Our results demonstrate higher ER mRNA levels in adipocytes compared to adipose stromal cells, whereas cytochrome P450 aromatase mRNA levels are higher in adipose stromal cells compared to adipocytes. The finding of ER mRNA in adipose tissue suggests the presence of the ER in adipose tissue. In addition the inverse correlation of ER mRNA and cytochrome P450 aromatase mRNA levels in adipocytes and adipose stromal cells suggests a paracrine relationship whereby estrogen produced by adipose stromal cells affects adjacent adipocytes.
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Estrogen has various effects on adipose tissue. Although the presence of estrogen receptor (ER) has been demonstrated in rat adipose tissue and adipocytes, ER has not been identified in human adipose tissue. In this study, we demonstrated the existence of ER protein and ER messenger RNA (mRNA) in human sc adipose tissue and adipocytes. The cytosol fraction of human adipose tissue was partially purified by ammonium sulfate precipitation, and the presence of ER protein was analyzed by [³H]estradiol (E2) binding assay and Western blot analysis. [³H]E2 binding assay showed a low specific binding due to high nonspecific binding, and the dissociation constant (Kd) and maximal binding sites could not be obtained by Scatchard analysis. Western blots, however, showed the presence of ER protein in both the partially purified cytosol and nuclear fractions of human adipose tissue. The mol wt of ER in both fractions was approximately 66,000. Furthermore, Northern blot analysis of total RNA samples isolated from human adipose tissue showed the expression of ER mRNA at 6.2 kilobase in size. ER mRNA was also identified in isolated human adipocytes by the reverse transcription and polymerase chain reaction. These results indicated that both ER protein and ER mRNA are expressed in human adipocytes, suggesting that the effect of estrogen on human adipose tissues might involve a direct action.
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Local production of estrogen in breast tissue may influence the growth of breast cancers. Peripheral conversion of C19 steroids to estrogens is catalyzed by the aromatase enzyme complex which is comprised of a specific form of cytochrome P450, aromatase cytochrome P450 (P450AROM) and the flavoprotein, NADPH-cytochrome P450 reductase. To evaluate P450AROM mRNA levels in breast tissue, a specific competitive polymerase chain reaction amplification procedure was devised. In this method, a rat P450AROM complementary RNA is coamplified as an internal standard in order to compare amplification reactions. The amplification products are recognized by hybridization with 32P-labeled oligonucleotides specific for each species. Densitometry is used to quantitate autoradiographs. Initial studies using RNA from whole breast tissue obtained from reduction mammoplasty revealed linearity of the relationship between the densitometer signal from the human amplification product and total RNA concentration. Breast tissue was then separated into a floating adipocyte fraction and a pelleted fraction containing the other cellular elements by collagenase digestion and centrifugation. Comparison of specific content of aromatase amplification product per unit weight of RNA extracted from adipocytes and pelleted cells revealed considerably higher levels in the RNA from the nonadipocyte fraction. Immunocytochemical characterization of this fraction revealed the presence of several cell types including macrophages, ductal epithelial cells, and endothelial cells, but primary cells of stromal origin.
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Endocrine changes resulting from the menopause transition dramatically modify women's hormonal milieu. The consequences of these changes not only lead to cessation of reproduction and accompanying symptoms in women, but also dramatically impact long-term health. Loss of estrogen has been associated with the development of cardiovascular disease. Central distribution and accumulation of adipose tissue, and the concomitant insulin resistant dyslipidemic state have emerged as important components of a cluster of metabolic abnormalities that are strongly related to coronary heart disease. Thus, estrogen deficiency may affect cardiovascular disease risk by mediating changes in body fat distribution. This article is an update of the literature in the area of menopause, hormone replacement therapy, and body fat distribution. Cross-sectional studies using anthropometric measurements of abdominal fat distribution most often failed to detect an effect of the menopause transition that was independent of advancing age and degree of obesity. The use of radiologic techniques such as DEXA and computed tomography, however, led to the conclusion that the menopause transition accelerates the selective deposition of intra-abdominal fat. Available longitudinal data also support an increase in central body fatness occurring with menopause. Most intervention trials on hormone replacement therapy and body fat distribution showed that the treatment prevented the increase in central adiposity that was noted in postmenopausal women receiving no treatment or placebo. These results are supported by retrospective studies that showed a lower WHR in hormone users vs non-users. Mechanisms potentially explaining the menopause-related acceleration in abdominal fat accumulation include changes in regional adipose tissue metabolism in the face of a positive energy imbalance. As some inconsistencies were found among studies, further investigations using longitudinal and intervention designs, as well as more precise methodologies to measure body fat distribution, are needed to clearly establish the effects of menopause and hormone replacement on abdominal body fat distribution and the concomitant increase in cardiovascular disease risk.
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Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested that the increased activity and expression of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) generating active cortisol from cortisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal cells (ASC) were used as in vitro models to investigate the tissue-specific regulation of 11βHSD1 expression and activity. Treatment with tumor necrosis factor-α (TNFα) caused a dose-dependent increase in 11βHSD1 activity in primary cultures of both sc [1743.1 ± 1015.4% (TNFα, 10 ng/ml); P < 0.05 vs. control (100%)] and omental [375.8 ± 57.0% (TNFα, 10 ng/ml); P < 0.01 vs. control (100%)] ASC, but had no effect on activity in human hepatocytes [90.2 ± 2.8% (TNFα, 10 ng/ml); P = NS vs. control (100%)]. Insulin-like growth factor I (IGF-I) caused a dose-dependent inhibition of 11βHSD1 activity in sc [49.7 ± 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [71.6 ± 7.5 (IGF-I, 100 ng/ml); P < 0.01 vs. control (100%)] stromal cells, but not in human hepatocytes[ 101.8 ± 15.7% (IGF-I, 100 ng/ml); P = NS vs. control (100%)]. Leptin treatment did not alter 11βHSD1 activity in human hepatocytes, but increased activity in omental ASC [135.8 ± 14.1% (leptin, 100 ng/ml); P = 0.08 vs. control (100%)]. Treatment with interleukin-1β induced 11βHSD1 activity and expression in sc and omental ASC in a time- and dose-dependent manner. 15-Deoxy-Δ12,14-PGJ2, the putative endogenous ligand of the orphan nuclear receptor peroxisome proliferator-γ, significantly increased 11βHSD1 activity in omental cells [179.7 ± 29.6% (1μ m); P < 0.05 vs. control (100%)] and sc [185.3 ± 12.6% (1 μm); P < 0.01 vs. control (100%)] ASC, and it is possible that expression of this ligand may ensure continued cortisol generation to permit adipocyte differentiation. Protease inhibitors used in the treatment of human immunodeficiency virus infection are known to cause a lipodystrophic syndrome and central obesity, but saquinavir, indinavir, and neflinavir caused a dose-dependent inhibition of 11βHSD1 activity in primary cultures of human omental ASC. 11βHSD1 expression is increased in human adipose tissue by TNFα, interleukin-1β, leptin, and orphan nuclear receptor peroxisome proliferator-γ agonists, but is inhibited by IGF-I. This autocrine and/or paracrine regulation is tissue specific and explains recent clinical data and animal studies evaluating cortisol metabolism in obesity. Tissue-specific 11βHSD1 regulation offers the potential for selective enzyme inhibition within adipose tissue as a novel therapy for visceral obesity.
Article
Context: The increasing prevalence of obesity is a major public health concern, since obesity is associated with several chronic diseases. Objective: To monitor trends in state-specific data and to examine changes in the prevalence of obesity among adults. Design: Cross-sectional random-digit telephone survey (Behavioral Risk Factor Surveillance System) of noninstitutionalized adults aged 18 years or older conducted by the Centers for Disease Control and Prevention and state health departments from 1991 to 1998. Setting: States that participated in the Behavioral Risk Factor Surveillance System. Main outcome measures: Body mass index calculated from self-reported weight and height. Results: The prevalence of obesity (defined as a body mass index > or =30 kg/m2) increased from 12.0% in 1991 to 17.9% in 1998. A steady increase was observed in all states; in both sexes; across age groups, races, educational levels; and occurred regardless of smoking status. The greatest magnitude of increase was found in the following groups: 18- to 29-year-olds (7.1% to 12.1%), those with some college education (10.6% to 17.8%), and those of Hispanic ethnicity (11.6% to 20.8%). The magnitude of the increased prevalence varied by region (ranging from 31.9% for mid Atlantic to 67.2% for South Atlantic, the area with the greatest increases) and by state (ranging from 11.3% for Delaware to 101.8% for Georgia, the state with the greatest increases). Conclusions: Obesity continues to increase rapidly in the United States. To alter this trend, strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.
Article
It has been reported that a high proportion of abdominal fat is associated with increased plasma androgen concentrations in women. Although less evidence is available, abdominal obesity appears to be associated with low plasma testosterone (T) levels in men. We have therefore examined in 80 men (aged 36.3 ± 3.2 years, mean ± SD) the correlations between body fatness, adipose tissue (AT) distribution measured by computed tomography (CT), and circulating levels of the following steroids measured by radioimmunoassay after extraction from serum and chromatography: dehydroepiandrosterone (DHEA), androstenedione (Δ4-DIONE), androst-5-ene-3β,17β-diol (Δ5-DIOL), T, estrone, and estradiol. Sex hormone—binding globulin (SHBG) levels were also determined. T, adrenal C19 steroids, and SHBG levels were negatively correlated with total body fatness indices and abdominal fat deposition measured by CT (−.23 ≤ r ≤ −.55, .0001 ≤ P ≤ .05) whereas estrone showed positive correlations with these body fatness and AT distribution indices. Covariance analysis showed that after control for the concentration of the adrenal steroid precursor Δ5-DIOL, there was no residual association between T levels and adiposity variables. Furthermore, multivariate analyses showed that steroid and SHBG levels could explain from 20% (visceral AT area measured by CT) to 40% and 42% (body mass index [BMI], waist circumference, and waist to hip ratio [WHR]) of the variation in adiposity variables (.0001 ≤ P ≤ .05), with Δ5-DIOL being the best single correlate of body fatness and abdominal fat deposition in men. On the other hand, total body fat mass was the best and sole predictor of DHEA, Δ5-DIOL, estradiol, and SHBG levels, explaining up to 22% of the variance (Δ5-DIOL). These results suggest that reduced concentrations of T and of adrenal C19 steroid precursors are associated with increased body fatness rather than with excess visceral fat accumulation. Furthermore, they emphasize the importance of adrenal steroids as correlates of body composition in men.