-
REVIEW
NAFLD as a Sexual Dimorphic Disease: Role of Genderand
Reproductive Status in the Developmentand Progression of
Nonalcoholic Fatty Liver Diseaseand Inherent Cardiovascular
Risk
Stefano Ballestri . Fabio Nascimbeni . Enrica Baldelli .
Alessandra Marrazzo . Dante Romagnoli . Amedeo Lonardo
Received: November 28, 2016 / Published online: May 19, 2017�
The Author(s) 2017. This article is an open access publication
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) spanssteatosis through
nonalcoholic steatohepatis,cirrhosis, and hepatocellular carcinoma
(HCC)associated with striking systemic features andexcess
cardiovascular and liver-related mortal-ity. The pathogenesis of
NAFLD is complex andmultifactorial. Endocrine derangements
areclosely linked with dysmetabolic traits. Forexample, in animal
and human studies, femalesex is protected from dysmetabolism thanks
toyoung individuals’ ability to partition fattyacids towards ketone
body production ratherthan very low density lipoprotein
(VLDL)-triacylglycerol, and to sex-specificbrowning of white
adipose tissue. Ovariansenescence facilitates both the development
ofmassive hepatic steatosis and the fibrotic pro-gression of liver
disease in an experimentaloverfed zebrafish model. Consistently,
estrogendeficiency, by potentiating hepatic inflamma-tory changes,
hastens the progression of diseasein a dietary model of
nonalcoholic steatohep-atitis (NASH) developing in
ovariectomizedmice fed a high-fat diet. In humans, NAFLDmore often
affects men; and premenopausalwomen are equally protected from
developingNAFLD as they are from cardiovascular disease.It would be
expected that early menarche, def-initely associated with estrogen
activation,would produce protection against the risk ofNAFLD.
Nevertheless, it has been suggested thatearly menarche may confer
an increased risk ofNAFLD in adulthood, excess adiposity being
theprimary culprit of this association. Fertile agemay be
associated with more severe hepatocyteinjury and inflammation, but
also with adecreased risk of liver fibrosis compared to menand
postmenopausal status. Later in life, ovar-ian senescence is
strongly associated with severesteatosis and fibrosing NASH, which
may occurin postmenopausal women. Estrogen deficiencyis deemed to
be responsible for these findingsvia the development of
postmenopausal meta-bolic syndrome. Estrogen supplementation mayat
least theoretically protect from NAFLDdevelopment and progression,
as suggested by
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Stefano Ballestri and Fabio Nascimbeni contributedequally and
are joint first authors.
S. BallestriAzienda USL di Modena, Pavullo Hospital, Pavullonel
Frignano, Italy
F. Nascimbeni � D. Romagnoli � A. LonardoOspedale Civile di
Baggiovara, AziendaOspedaliero-Universitaria di Modena, Modena,
Italy
F. Nascimbeni (&) � E. Baldelli � A. MarrazzoDepartment of
Biomedical, Metabolic and NeuralSciences, University of Modena and
Reggio Emilia,Modena, Italye-mail: [email protected]
Adv Ther (2017) 34:1291–1326
DOI 10.1007/s12325-017-0556-1
http://www.medengine.com/Redeem/2128F060377C0C79http://www.medengine.com/Redeem/2128F060377C0C79http://crossmark.crossref.org/dialog/?doi=10.1007/s12325-017-0556-1&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1007/s12325-017-0556-1&domain=pdf
-
some studies exploring the effect of hormonalreplacement therapy
on postmenopausalwomen, but the variable impact of different
sexhormones in NAFLD (i.e., the pro-inflammatoryeffect of
progesterone) should be carefullyconsidered.
Keywords: Fibrosis; Hormones; Inflammation;Man; Menarche;
Menopausal status; NASH;Physiopathology; Sex; Steatosis; Women
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD)encompasses the whole
spectrum of (predomi-nantly) steatogenic liver disorders
spanningsteatosis through nonalcoholic steatohepatitis(NASH),
cirrhosis, and hepatocellular carci-noma (HCC) [1–3], associated
with strikingsystemic features [4, 5] and excess cardiovascu-lar
and liver-related mortality [6–9]. Histologi-cally
indistinguishable from alcoholic liverdisease, and nevertheless
observed in the non-alcoholic individual [10], NAFLD is
closelylinked with insulin resistance (IR) [11]
and,bidirectionally, with the metabolic syndrome(MetS) of which it
may be both a cause and aconsequence [12, 13]. A leading cause
ofchronic liver disease worldwide and affectingone out of four
individuals in the European andnorth-American general populations
[14],NAFLD is highly prevalent in certain groups ofindividuals
carrying either the full-blown orindividual traits of the MetS
[15]. Moreover,NAFLD carries an excess of
health-relatedexpenditures owing to its close connectionswith
progressive liver disease and car-dio-metabolic morbi-mortality [9,
16–19].
The pathogenesis of NAFLD has variablybeen conceptualized as
two-hit [20], a one-hit[11], or a multistep process [21], and the
last ispresently the most widely accepted pathogenicmodel. In its
original definition, a first hit leadsto steatogenesis and a second
one to fibrosis[22]. However, metabolic factors, and particu-larly
IR, invariably account for most of the ele-mentary NAFLD histologic
lesions in humans,indirectly supporting the outdated and yet
conceptually more parsimonious ‘‘one-hit’’theory [11, 12].
Evidence both in animals and humans sup-ports the notion that
female sex is protectedfrom dysmetabolic traits thanks to young
indi-viduals’ ability to partition fatty acids towardsketone body
production rather than very lowdensity lipoprotein
(VLDL)-triacylglycerol [23],and to sex-specific browning of white
adiposetissue which contributes in protecting femalemice from
experimental NAFLD associated withmethionine choline deficient diet
[24].
In 1980, Ludwig reported that NASH wascommon among elderly women
with metaboliccomorbidity [25]. However, we now know thatNAFLD more
often affects men [15, 26] and thatpremenopausal women are equally
protectedfrom NAFLD development as they are fromcardiovascular
disease (CVD) [27, 28]. Recentstudies in the overnourished
zebrafish modelhave shown that ovarian senescence,
viahypoestrogenemia, facilitates both the devel-opment of massive
hepatic steatosis and thefibrotic progression of liver disease
[29]. Con-sistently, estrogen deficiency, by potentiatinghepatic
inflammatory changes, hastens theprogression of disease in a
dietary model ofNASH developing in ovariectomized mice fed
acholesterol-rich hyperlipidic diet [30]. Collec-tively, these
findings suggest that hormonalchanges, rather than those multiple
physiologicderangements associated with aging per se [31],are a
major determinant of progressive NAFLDin human menopause.
Obesity and obesity-related diseases, such astype 2 diabetes
(T2D), MetS, and atherosclerosis,are complex conditions driven by
genetic andenvironmental factors, in which a sexualdimorphism has
been clearly established. Here,we have reviewed current evidence
suggestingthat NAFLD is a sexually dimorphic condition,too. We
hypothesized that the higher incidenceof disease in men and the
worse outcome inpostmenopausal women, i.e., the
‘‘sexualdimorphism’’ of NAFLD, might offer clues use-ful in
expanding our understanding of thepathogenesis and providing hints
for preven-tion and treatment of NAFLD. Given thepotential research
and clinical implications ofsexual dimorphism in NAFLD, we carried
out a
1292 Adv Ther (2017) 34:1291–1326
-
systematic review of the literature by using thefollowing
keywords: steatosis OR fatty liverAND gender OR sex OR menopause.
On thesegrounds, this narrative review is aimed tohighlight how sex
modulates the developmentand progression of NAFLD and to pinpoint
whatthe role of menarche and menopause is. Specialemphasis is
conferred to CVD risk. The rela-tionship of polycystic ovary
syndrome (PCOS)to NAFLD has recently been covered elsewhere[32] and
is outside the scope of this review.
Compliance with Ethics Guidelines
This article is based on previously conductedstudies and does
not involve any new studies ofhuman or animal subjects performed by
any ofthe authors.
EPIDEMIOLOGY OF NAFLD
Gender and reproductive status modulate therisk of developing
NAFLD and NASH with/without advanced fibrosis [15].
Risk of NAFLD
IncidenceEvidence from longitudinal studies suggeststhat the
incidence of NAFLD is higher in themale as compared to the female
gender(Table 1) [33–43]. One study investigating theincidence of
NAFLD in women as a function ofreproductive status found incidence
to behigher in menopausal (7.5%)/postmenopausal(6.1%) women as
compared to premenopausal(3.5%) women. However, postmenopausal
sta-tus was associated with an increased risk ofincident NAFLD at
univariate but not at multi-variate analysis adjusted for age,
metabolicsyndrome, and weight gain [37]. The incidenceof NAFLD in
women taking hormonal replace-ment therapy (HRT) (5.3%) was higher
than inpremenopausal (3.5%) women but lower thanin menopausal women
(7.5%). HRT was notassociated with increased risk of incidentNAFLD
either at univariate or at multivariateanalysis [37]. Indeed other
longitudinal studies
suggest that estrogens are a protective factor forthe
development of NAFLD. An Italian multi-centric study on 5408
healthy women who hadhad hysterectomies, randomly assigned
toreceive tamoxifen (an estrogen inhibitor) orplacebo for 5 years,
showed that tamoxifen wasassociated with higher risk of development
ofNAFLD/NASH especially in overweight/obesewomen [44]. Finally a
small double-blind, ran-domized placebo-controlled trial on 50
womenwith T2D showed that HRT containing low-doseestradiol and
norethisterone significantlyreduced serum levels of liver function
enzymes,potentially owing to a reduced liver fat accu-mulation
[45].
Overall, data from epidemiological longitu-dinal studies have
shown a key role of weightgain, presence of MetS and its single
traits asindependent predictors of the development ofNAFLD [33–43].
Notably, some studies havefound that male sex was associated with
inci-dent NAFLD independently of age and meta-bolic factors [33,
35, 41]. Moreover, two Asianstudies have reported a specific role
of ageaccording to gender and reproductive status inmodulating the
risk of incident NAFLD. Onestudy showed that age was an
independentpredictor for developing NAFLD only in females[34] and
the other one reported that ageincreased the risk for incident
NAFLD in pre-menopausal but not in postmenopausal women[37].
PrevalenceDespite preliminary studies reporting a higherrisk of
NAFLD in females, a large body of evi-dence now definitely supports
the notion thatthe prevalence of NAFLD is higher in men thanin
women and that gender-specific differencesexist in relation to age
(Table 1)[33, 37, 41, 46–77]. Conflicting with the abovenotion, two
large sample community Iranianstudies reported a higher prevalence
of NAFLDin women than in men [70, 74]. However, thesefindings
might, at least in part, be accounted forby women having markedly
higher rates ofprevalence of obesity compared to men in
thesestudies. Consistent with the view reportedabove, a higher
prevalence of fatty liver has
Adv Ther (2017) 34:1291–1326 1293
-
Table1
Genderim
pactson
incident
andprevalentNAFL
D.E
videncefrom
longitudinalandcross-sectionalstudies
Stud
yMetho
dFind
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofFL
Incidence(lon
gitudinal
stud
ies)
Independ
ent
predictors
Kojim
a
etal.[33]
35,519
Japanese
subjects(health
check-up),65.2%M,m
eanage
45.8years,F-up
12years
US
14.3%
Msex(O
R1.7),
metabolicfactors
(BMIOR6.3)
Msexandmetabolicfactorsare
independ
entrisk
factorsforthe
incidenceof
NAFL
D
Ham
aguchi
etal.[34]
3147
healthyJapanese
(1694M),aged
21–8
0years,
meanF-up
414days
US
10%;in
M(14%
)[F(5%)
Age
(onlyin
F),w
eight
gain,and
MetS
NAFL
Dismoreincident
inmen
than
inwom
en
Suzuki
etal.
[35]
1537
Japanese
subjects
(1352M),meanage35
years,
meanF-up
60months
AST
,ALT
31/1000person-years
Msexoverallandin
subjects\40
years
(HR4.6);metabolic
factors
Msexandmetabolicfactorsare
independ
entrisk
factorsforthe
incidenceof
NAFL
D
Tsuneto
etal.[36]
1635
Nagasakiatom
icbomb
survivors(606
M),meanage
63years,F-up
11.6years
US
19.9/1000person-years(22.3in
M[
18.6in
F);M
(38%
)[F
(25%
)before
50years
Obesity,h
ypertension,
andhigh-TG
(gender
NS)
Genderisnotan
independ
entrisk
factor
forincident
NAFL
D
Ham
aguchi
etal.[37]
1603
Japanese
wom
en,aged
21–8
0years,meanF-up
414days
US
5%in
F;in
postmenopausal
(6.1–7
.5%)andun
derHRT
(5.3%)[
prem
enopausal
(3.5%)
Age
(onlyin
prem
enopausal),
weightgain,and
MetS
Thereisagradient
intheincidenceof
NAFL
Din
wom
en:
postmenopausal[
HRT[
prem
enopausal
Zhouet
al.
[38]
507Chinese
NAFL
D-free
participants,m
edianF-up
4years
US
9.1%
;in
M7.3%
[F9.7%
Age,m
etabolicfactors
(genderNS)
Genderisnotan
independ
entrisk
factor
forincident
NAFL
D
Zelber-Sagi
etal.[39]
147Israelisubjects,m
eanage
51.2years,F-up
7years
US
19.0%
(2.7%/year)
Weightgain
and
HOMA
(genderNS)
Genderisnotan
independ
entrisk
factor
forincident
NAFL
D
Sung
etal.
[40]
2589
Koreansubjects,m
ean
F-up
4.37
years
US
34.7/1000person-years;in
M
(23.4%
)[F(9.7%)
MetStraits(genderNS)
Genderwas
notan
independ
entrisk
factor
forincident
NAFL
D
Xuet
al.
[41]
5562
non-obeseChinese
subjects,m
eanage43
years,
F-up
5years
US
8.9%
Msex,youn
gerage,and
metabolicfactors
Msexisarisk
factor
fortheincidence
ofNAFL
Dat
multivariateanalysis
1294 Adv Ther (2017) 34:1291–1326
-
Table1
continued
Stud
yMetho
dFind
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofFL
Incidence(lon
gitudinal
stud
ies)
Independ
ent
predictors
Wonget
al.
[42]
565HongKongsubjects,m
ean
age48
years,medianF-up
47months
1 HNMR
3.4%
/year
MetS(M
sexpredictor
onlyat
univariate
analysis)
Msexisarisk
factor
fortheincidence
ofNAFL
Dat
univariate
analysis
Yun
etal.
[43]
37,130
Koreansubjects,m
ean
age(M
39.4,F
38.6years),
46%
M,F
-up2years
US
M(44.5/1000
person-years)[
F
(20.4/1000
person-years)
WC
gain
inboth
sexes
Visceralobesitystronglypredicts
NAFL
Din
either
gend
er
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Kojim
aet
al.[33]
39,151
Japanese
subjects(health
check-up),meanage45.8years,
61%
M
US
M(26%
)[F(12.7%
)NA
NAFL
Dismore
prevalentin
M
gend
er
Shen
etal.[46]
4009
Chinese
administrative
officersnon-drinkers,aged
20–8
1years,64%
M
US
M(13.3%
)[F
(2.7%)before
50years;similar
after50
years
Msex,age[
50years,
andmetabolictraits
Msexandmetabolic
factorsare
independ
entrisk
factorsforthe
prevalence
of
NAFL
D
Fanet
al.[47]
3175
Chinese
subjectsfrom
Shanghai,m
eanage52years,
38.4%
M
US
M(19.2%
)[F
(11.3%
)before
50years;F[
M
after50
years
Msex(O
R2.7)
and
metabolicfactors
Msexandmetabolic
factorsare
independ
entrisk
factorsforthe
prevalence
of
NAFL
D
Adv Ther (2017) 34:1291–1326 1295
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Chenet
al.[48]
3245
adultsin
aTaiwan
rural
village,agedC18
years,45.3%
M
US
M(19.7%
)[F
(10.7%
)
Msexandmetabolic
factors;
ageC65
years
negative
predictor
Msexandmetabolic
factorsare
independ
entrisk
factorsforthe
prevalence
of
NAFL
D
Park
etal.[49]
6648
Koreansubjects,
aged
C20
years,53%
M
US
M(22.6%
)[F
(6.8%)before
50years;similar
after50
years
Menopausestatus
and
increasing
agein
F
Menopauseisastrong
risk
factor
for
prevalentNAFL
D
Zelber-Sagi
etal.[50]
352Israelisubjects,m
eanage
51years,53.4%
M
US
M(38%
)[F(21%
)M
sex(after
adjustmentfor
obesity)
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Zhouet
al.[51]
3543
inhabitantsof
6urbanand
ruralareasin
China,
aged[7years,37%
M
US
M(13.8%
)[F
(7.1%)before
50years;the
opposite
after
50years
Msexandmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Liet
al.[52]
9094
Chinese
subjects(m
edical
check-up),aged[18
years,52%
M
US
M(18.9%
)[F
(5.7%);increased
withagein
both
sexes\
50years
Msex,increasing
age,
BMI,andother
MetSfeatures
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
1296 Adv Ther (2017) 34:1291–1326
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Caballeriaet
al.[53]
766Spanishindividuals,aged
17–8
3years,33.4%
M
US
M(42.2%
)[F
(20.3%
)
Msex,increasing
age,
andmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Huet
al.[54]
7152
employeesof
Shanghai
work-un
its,aged
18–6
5years,
60.5%
M
US
M[
Fin
thesame
agegroup,
peaking
at50–6
5years;in
F[
50years
doubled
HighTG
levelwas
thestrongest
predictorin
M
whileobesitythe
strongestonein
F
Riskfactorsfor
prevalentNAFL
D
aregend
er-specific
Wonget
al.[55]
922individualsfrom
HongKong
population,aged19–7
2years,
58%
F
1 HMRS
M(36.8%
)[F
(22.7%
);in
M
peakingat
40years;
inFincreasing
after
menopause
Metabolicfactors(M
sexandolderage
NS)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Ham
aguchi
etal.[37]
4401
Japanese
subjects(health
check-up),aged
21-80years,
51.6%
men
US
M(24%
)and
postmenopausalF
(15%
)[remenopausalF
(6%);increased
withagein
Fonly
Postmenopause
and
HRT
NS(age
and
MetSadjusted);
agingin
prem
enopausalF
only(weightgain
andMetSadjusted)
MenopauseandHRT
arenot
independ
entrisk
factorsforprevalent
NAFL
D
Eguchiet
al.[56]
8352
Japanese
subjects(health
check-ups),aged21–8
6years,
51.8%
M
US
M[
Fat
allages
Metabolicfactors
(age[50
yearsin
F
only)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Adv Ther (2017) 34:1291–1326 1297
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Younossiet
al.[57]
11,613
American
participants
(from
NHANESIII)
US
19%
Fsexandyoun
gerage
forlean
NAFL
D;
theopposite
for
NAFL
Dwith
BMIC25
Fsexisarisk
factor
forlean
NAFL
D
Lazoet
al.[58]
12,454
American
subjects(from
NHANESIII),aged
20–7
4years
US
M(20.2%
)[F
(15.8%
)
Prevalence
inM
(20.2%
)[F
(15.8%
)(adjusted
forage,race,B
MI,
T2D
)
Mgend
eris
associated
withan
increasedNAFL
D
prevalence
Wanget
al.[59]
4226
Chinese
subjects[60
years
vs3145
controls\60
yearsfrom
thesamecohort
US
M(32%
)[F(9%)
before
60years;
similarafter
60years
Msex(onlyin
those\
60years)
andmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Xuet
al.[41]
6905
non-obese(BMI\
25)
Chinese
subjects,6
3%M
US
7.3%
Msex,youn
gerage,
andmetabolic
factors
Msexandmetabolic
factorsare
independ
entrisk
factorsforprevalent
NAFL
D
Yan
etal.[60]
3762
Chinese
residents,aged
20–9
2years,61.9%
M
US
M(45%
)[F(30%
);
higher
before
50yearsbutsimilar
after
Metabolicfactors(M
sexpredictedonly
atun
ivariate
analysis)
Msexisarisk
factor
forprevalent
NAFL
Dat
univariate
analysis
only
1298 Adv Ther (2017) 34:1291–1326
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Chiloiroet
al.[61]
2974
SouthItaliansubjects,aged
30–8
9years,56.5%
M
US
M(37%
)[F(26%
)MetSanditsfeatures,
BMI,visceral,and
subcutaneous
fatin
both
MandF
Riskfactorsfor
prevalentNAFL
D
arenot
gend
er-specific
Foster
etal.[62]
3056
American
multiethn
ic
subjects,m
eanage63
years,55%
F
CT
NA
Fsexprotective
inall
andAAs;notin
Caucasiansand
Hispanics.Y
ounger
agein
all,
Caucasiansand
Hispanics;notin
AAs
Fsexisspared
from
prevalentNAFL
D
Yanget
al.[63]
2256
Chinese
subjects(health
check-up),meanage62.04years,
87.9%
M
US
M(28.4%
)[F
(20.3%
)
Younger
age,RDW
andmetabolic
factors(genderNS)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Saidaet
al.[64]
3110
Japanese
subjects(health
check-up),aged
C30
years,
59.5%
M
US
M(45%
)[F(23%
)Weightgain
C10
kg
sincetheageof
20yearsregardless
ofsex
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Wanget
al.[65]
25,032
Chinese
subjects(health
check-up),aged
18–9
4years,
62%
M
US
M(32%
)[F(13%
);
similarin
both
sexes[
60years
Metabolicparameters
inboth
sexes;
increasing
age
(C60
years)onlyin
F
Riskfactorsfor
prevalentNAFL
D
arenot
gend
er-specific
Adv Ther (2017) 34:1291–1326 1299
-
Table1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Schn
eideret
al.[66]
4037
non-Hispanicwhite,2
746
non-Hispanicblack,
and2892
Mexican–A
merican
adultsin
theNHANESIII
US
M(15%
)[F(10%
)
among
non-Hispanic
whitesonly
(age-adjusted)
Genderdifference
still
significant
after
adjustmentfor
BMIandWC
Mgend
eris
associated
withan
increasedNAFL
D
prevalence
independ
entof
visceralobesity
Xiaoet
al.[67]
18,676
Chinesesubjects,m
eanage
40.6years,55.4%
M
US
M(33%
)[F(8%)
Msexandmetabolic
factors
Msexisan
independ
entrisk
factor
forprevalent
NAFL
D
Martı́nez-Alvaradoet
al.[68]
846Mexican
subjects,m
eanage
53years,49.3%
M
CT
M(36.5%
)[F
(28.4%
)
Metabolicfactors
(MetSin
Fonly)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Liu
etal.[69]
11,200
Chinese
gallstone-free
subjects,4
6.7%
M
US
M(31%
)[F(13%
)NA
NAFL
Dismore
prevalentin
M
gend
er
Amirkalaliet
al.[70]
5023
Iranianparticipants,m
ean
age45.35years,56.7%
M
US
F(46%
)[M
(42%
);
peakingin
M
40–6
0years,in
F[60
years
Age,M
etS,
andits
factors(higherORs
inF)
Genderisnotan
independ
entrisk
factor
forprevalent
NAFL
D
Nishiojiet
al.[71]
3271
Japanese
subjects(health
check-up),44.2%
M
US
M[
Fforallages,
except
in
obeseC70
years
Metabolicfactorsin
MandF
Riskfactorsfor
prevalentNAFL
D
arenot
gend
er-specific
Huang
etal.[72]
8626
Chinese
subjectsC40
years
US
M(28.7%
)*
F
(28.1%
)
NA
Nogend
erspecific
difference
in
prevalentNAFL
D
1300 Adv Ther (2017) 34:1291–1326
-
been also observed in male obese children andadolescents than in
female ones [78].
Men commonly display an increasingprevalence of NAFLD during
adulthood fromyoung to middle-age, describing an ‘‘invertedU-shaped
curve’’ which starts declining after theage of 50–60 years [47,
56]. In women of fertileage, the prevalence of NAFLD is lower than
inmen owing to the putative protective effect ofestrogens which,
however, wanes after themenopause. Accordingly, the prevalence
ofNAFLD in women rises after the age of 50 years,peaks at 60–69
years, and declines after 70 years[47, 54, 56]. As a result of
this, after the fifthdecade, postmenopausal women compared tomen of
the same age have a similar[46, 49, 60, 65] or even higher [47, 51]
preva-lence of NAFLD. In agreement with these find-ings, a
multicenter study from northern Italyfound that men with NAFLD were
approxi-mately 10 years younger than women with thiscondition [79],
a finding compatible with thehypothesis that premenopausal women
are‘‘protected’’ from developing NAFLD. Con-versely, NAFLD is more
prevalent in post-menopausal [37, 80–82] and PCOS-affectedwomen
than premenopausal ones [80]. Consis-tently, a large
cross-sectional population-basedsurvey in northeast Germany on 808
womenaged 40–59 years showed that menopause statuswas independently
associated with hepaticsteatosis after adjustment for metabolic
factors[83]. Interestingly, women with NAFLD exhibita significantly
lower concentration of serumestradiol, which is the principal
active estrogen,than NAFLD-free (premenopausal, post-menopausal,
and PCOS) controls [80]. A lowerprevalence of NAFLD, as well as of
MetS, hasbeen reported in postmenopausal womenreceiving HRT
compared to those not receivingit, which suggests that HRT probably
protectsfrom NAFLD. Moreover, in this study post-menopausal women
with NAFLD who receivedHRT had lower frequency of insulin
resistanceas well as MetS and showed reduced serumlevels of liver
enzymes and ferritin [84].
Most studies using multivariate analysis haveshown that male sex
is associated with anincreased prevalence of NAFLD independentlyof
age and metabolic conditionsT
able1
continued
Stud
ypo
pulation
Diagnosisof
FLPrevalence
(cross-section
alstud
ies)
Independ
ent
predictors
Fattahiet
al.[73]
2980
Iraniansubjects,
aged
C18
years,31.3%
M
US
M(32.9%
)[F
(27.4%
)
NA
NAFL
Dismore
prevalentin
M
gend
er
Motam
edet
al.[74]
5052
Iraniansubjects,
aged
C18
years,56.6%
M
US
F(44.2%
)[M
(40.1%
)
Age,m
etabolic
factors;Fsex
protective
Fsexisspared
from
prevalentNAFL
D
AAsAfrican-Americans,BMIbody
massindex,Ffemale/s,FL
fattyliver,F
-upfollow-up,
1 HMRSproton
magneticresonancespectroscopy,H
OMAhomeostasis
modelassessment,HRThorm
onereplacem
enttherapy,M
male/s,MetSmetabolicsynd
rome,NAnotassessed,N
AFL
Dnonalcoholicfattyliverdisease,NHANES
IIINationalHealth
andNutrition
ExaminationSurvey
III,NSnotsignificant,O
Rodds
ratio,RDW
redbloodcelldistribution
width,T
2Dtype
2diabetes,T
Gtriglycerides,USultrasound
,WCwaistcircum
ference
Adv Ther (2017) 34:1291–1326 1301
-
[41, 46, 48, 50, 51, 53, 58, 62, 63, 66, 67, 74].Some studies
have shown an independent,positive association between NAFLD
andincreasing age in both sexes [46, 50–53, 70, 74]or in females
only [65], while others reported aninverse association [41, 48, 62,
63]. At variance,other studies have shown that sex differences
inthe prevalence of NAFLD were mostly accoun-ted for by metabolic
factors [36, 37, 55, 56, 60,63, 64]. Finally, some studies failed
to investi-gate the role of gender given that a
separatemultivariate analysis according to sex was notperformed
[34, 49, 54, 56, 61, 65, 68, 70, 71].
In addition to and independent of the role ofMetS and its
components, menopausal status[49, 83, 85] and increasing age [49,
56, 82] haveall been consistently identified as strong riskfactors
for NAFLD in women. Only in a fewstudies was the association
between menopau-sal status and NAFLD no longer significant
afteradjustment for age and metabolic factors[37, 81], indicating
that menopause predisposesto developing NAFLD via incident
dysmetabolictraits which typically appear in the post-menopausal
age.
A recent cross-sectional study conducted in apopulation of
postmenopausal women con-cluded that MetS, abdominal obesity, and
IR arerisk factors for the development of NAFLD whilehigher
adiponectin levels protect from devel-oping it [86]. These findings
indicate thatNAFLD modifiers in this specific population ofwomen
closely mirror those found in the gen-eral population.
In lean subjects [body mass index (BMI) lessthan 25 kg/m2)]
NAFLD has been associatedwith younger age [41, 57] and either male
[41]or female gender [57].
Risk of NASH and Fibrosis Progression
One large sample study based on an electronichealth file
database reported that the risk of‘‘recorded’’ NAFLD/NASH diagnosis
increasedlinearly with BMI, was higher in males thanfemales and in
those with T2D [87]. However, theproportion of true NASH cases
among the ‘‘recor-ded’’ diagnosis of NAFLD/NASH was unclear.
A longitudinal study in subjects with biop-sy-proven NAFLD found
that sex was not anindependent risk factor for the progression
offibrosis [88]. In agreement, a systematic reviewhas shown that
age and hepatic necroinflam-mation are the only independent
predictors ofthe development of advanced fibrosis in NASHpatients,
while other parameters such as MetSfeatures and sex are not
[89].
However, conflicting with the above studies,data from
cross-sectional studies (Table 2)[29, 57, 65, 90–97], which are
based, in themajority of cases, on a histological diagnosis ofNASH,
tend to suggest that the risk of NASH andadvanced fibrosis is
indeed higher in femalesthan males independent of metabolic
factors[65, 90, 93, 94], and only a few studies conflictwith the
above findings [91, 92, 95].
As is easily foreseeable, obese and post-menopausal women,
compared to pre-menopausal and non-obese women, suffer froma
remarkably higher prevalence of NAFLD andNASH as a result of a
worse metabolic profile[82]. At variance, a recent study reported
that,compared to men and postmenopausal women,the risk of lobular
inflammation and hepatocyteinjury was significantly increased both
in pre-menopausal women and in those taking syn-thetic hormones
such as oral contraceptives andHRT [97]. Given the supposed effects
of estro-gens on metabolic health and liver injury, thefindings of
this study appear counterintuitive. Itis noteworthy that the study
by Yang et al. hasseveral limitations, including some
importantsources of potential bias, such as the
restrictedenrollment at tertiary academic centers, meno-pausal
category and synthetic hormone usewere self-reported, and
information on cumu-lative estrogen and/or progesterone exposureand
serum hormonal levels were lacking. Ofnote, the authors highlight
that, despiteincreased liver injury and inflammation,
pre-menopausal women were at decreased risk ofliver fibrosis
compared with men and post-menopausal women. Moreover,
sensitivityanalyses separately assessing the impact of
pro-gesterone use and estrogen use clearly suggestedthat only the
former was associated with liverdamage. Collectively these findings
provide
1302 Adv Ther (2017) 34:1291–1326
-
Table2
Impact
ofgend
eron
NASH
/fibrosisprevalence
Stud
yMetho
dCross-section
alstud
ies
Find
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofNASH
Prevalence
Independ
entpredictors
Singhet
al.
[90]
71consecutive
Asian-Ind
ianNASH
patients,aged9–
57years,
76.1%
M
Biopsy
NA
Fsexforfibrosisstage
Fsexisan
independ
ent
risk
factor
forfibrosis
Hossain
etal.[91]
432American
NAFL
D
patients,m
eanage
43.6years,22.9%
M
Biopsy
26.8%
NASH
and
17.4%
moderate-to
severe
fibrosis
MsexforNASH
andmoderate-to-severefibrosis
inaddition
toethn
icity,ALT,A
ST,m
etabolic
factors
Mgend
erisastrong
independ
entrisk
factor
forboth
NASH
and
fibrosis
Al-h
amoudi
etal.[92]
1312
SaudiArabian
inpatients,m
eanage
44.7years,51.0%
M
US
16.6%
NASH
(by
ALT[60
U/L)
Msex,youn
gageandlowtotalCH
predicted
high
ALT
inNAFL
D
Mgend
erisastrong
independ
entrisk
factor
for
hypertransam
inasem
ic
NAFL
D
Bam
bha
etal.[93]
1026
adults(N
ASH
CRN
Database),m
eanage
48.8years,37%
M
Biopsy
61%
NASH
and29%
advanced
fibrosis
FsexforNASH
andadvanced
fibrosis;increasing
ageforadvanced
fibrosis;plus
metabolicfactors
Fsexisan
independ
ent
risk
factor
forNASH
andfibrosis
Younossi
etal.[57]
11,613
American
participants(from
NHANESIII)
US
12%
NASH
(bygrade
2–3US-FL
?high
ALT,A
ST,and
/or
T2D
/IR)
Younger
ageandmetabolicfactors(genderNS)
Genderisnotan
independ
entrisk
factor
forNASH
Tapperet
al.
[94]
358NAFL
Dpatients,
62.9%
M
Biopsy
NASH
andadvanced
fibrosis[
inFvs
M
(45%
vs30%;23%
vs
14%)
Fsex,BMI,andALTforNASH
;age,AST
,and
APR
Iforadvanced
fibrosis
Fsexisan
independ
ent
risk
factor
forNASH
andfibrosis
Adv Ther (2017) 34:1291–1326 1303
-
Table2
continued
Stud
yMetho
dCross-section
alstud
ies
Find
ings
Con
clusion
Stud
ypo
pulation
Diagnosis
ofNASH
Prevalence
Independ
entpredictors
Wanget
al.
[65]
25,032
Chinese
subjects
(health
check-up),aged
18–9
4years,62%
M
US
NASH
withadvanced
fibrosis(byBAAT
score,AST
/ALT)[
Fvs
M
NA
Prevalence
ofNASH
with
advanced
fibrosisis
higher
inFsex
Yanget
al.
[95]
541American
patientswith
NASH
,meanage48
years,35.1%
M
Biopsy
100%
NASH
;22%
advanced
fibrosis
Msex,postmenopausalFstatus
(premenopausal
Freference;borderlin
eP),p
re-T2D
/T2D
for
fibrosis
Msexandpostmenopausal
status
areindepend
ent
risk
factorsforfibrosing
NASH
Turolaet
al.
[29]
244females
and244
age-matched
males
with
NAFL
D
Biopsy
F2–F
4fibrosis
Menopause,m
etabolicfactors,andNASH
for
F2–F
4fibrosisin
FwithNAFL
D
Menopause
isstrongly
associated
withfibrosing
NASH
Klairet
al.
[96]
488postmenopausal
NAFL
Dsubjects
Biopsy
Advancedfibrosis
38.4%
inprem
ature
menopause
Fvs
32.7%
inotherF
Prem
aturemenopause
andtimefrom
menopause
foradvanced
fibrosis(adjustedforage,race,
metabolicfactors)
The
longer
theduration
of
postmenopausalstatus
thehigher
therisk
of
NASH
Yanget
al.
[97]
1112
American
NAFL
D
patients(160
prem
enopausaland489
postmenopausalF;
463M)
Biopsy
NASH
[in
pre/postmenopausal
F(62%
)vs
M(50%
)
Lobular
inflammationrisk
increasedin
(1)
prem
enopausalF[
MandpostmenopausalF,
(2)oralcontraceptives
andHRT
users
(adjustedforcovariatesof
livermetabolicstress)
Fertile
ageandestrogen
use
may
predispose
tomore
necroinfl
ammatory
NASH
variants
ALTalanineam
inotransferase,A
STaspartateam
inotransferase,A
PRIAST
-to-plateletratioindex,BMIbody
massindex,Ffemale/s,FL
fattyliver,F-upfollow-up,
HRT
horm
onereplacem
enttherapy,
Mmale/s,MetSmetabolic
synd
rome,
NA
notassessed,NAFL
Dnonalcoholic
fattyliver
disease,
NASH
nonalcoholic
steatohepatitis,NHANESIIINationalHealth
andNutrition
ExaminationSurvey
III,NSnotsignificant,T2D
type
2diabetes,USultrasound
,WC
waist
circum
ference,yearsyears
1304 Adv Ther (2017) 34:1291–1326
-
novel hints regarding a potential multifacetedimpact of sex
hormones in NAFLD.
Consistent with the hypothesis that estro-gens do exert a
beneficial effect on NAFLD,menopause has been independently
associatedwith significant fibrosis both in women withNAFLD and in
an experimental zebrafishsteatosis model [29]. A recent study has
shownthat men display a higher risk of advancedfibrosis compared to
premenopausal women,while after menopause both sexes show a
simi-lar severity of liver fibrosis, suggesting thatestrogens
protect from the development offibrosis [95]. A subsequent study
limited tonon-obese women with biopsy-proven NAFLDconfirmed that,
even in non-obese NAFLDpatients, postmenopausal women still had
moresevere fibrosis, when compared to pre-menopausal subjects [98].
Accordingly, a studyconducted in 488 postmenopausal women
withbiopsy-proven NAFLD has shown that, inde-pendently of age and
metabolic factors, thelonger the estrogen deficiency in
post-menopausal status is (i.e., premature meno-pause and time from
menopause), the higherthe risk of fibrosis is [96].
The role of gender in influencing liver-re-lated mortality in
NAFLD is still uncertain,although some studies have reported that
menare at an increased risk [99–101].
Risk of Hepatocellular Carcinoma
A universal feature of HCC is the striking maleprevalence, with
a male/female ratio averaging2:1 to 7:1; the latter proportion is
more oftenfound in HBV-related HCC [102]. Nevertheless,compared to
viral etiologies of HCC,NAFLD-related HCC was found to be
associatedwith the lowest male/female ratios in one study[103].
NAFLD-related HCC may also occur innon-cirrhotic livers, but this
seems to be morelikely in men [104]. The sexual dimorphism inHCC is
also maintained regarding prognosis,with women showing better
survival rates[102, 105]. However, menopause seems toattenuate
these advantages [102, 105].
In summary, the incidence of NAFLD ishigher in men than in
women, and some
longitudinal studies indicate that male gender isan independent
predictor of NAFLD develop-ment. The prevalence of NAFLD is
globallyhigher in men than women, but after meno-pause women
display a similar or even a higherprevalence compared to men, a
finding sup-porting a protective effect of estrogens.
Incross-sectional studies, male gender and meno-pausal status have
often been associated withthe risk of NAFLD, independent of age
andmetabolic factors. The prevalence of NASH andadvanced fibrosis
has been found to be higherin postmenopausal women than in men;
how-ever, longitudinal studies have failed to supporta role for
gender in influencing the progressionof liver fibrosis. Finally,
HCC is definitely morecommon in men than in women in cases due
toviral etiology; NAFLD may probably lower themale/female ratio in
the risk of developing HCCand it is possible that gender affects
the prog-nosis of HCC.
NAFLD AND CVD
NAFLD is increasingly recognized as a multi-system disease [5].
A growing body of evidencesuggests that NAFLD (assessed by liver
enzymes,imaging, or biopsy) is associated with increasedincidence
and prevalence of subclinical andclinical CVD, mainly coronary
heart disease(CHD), independently of age, gender, andmetabolic
factors, as recently reviewed in detailelsewhere [106, 107]. In the
general population,male sex is more prone to incident CHD underthe
age of 50 years compared to women but,after menopause, the
incidence in women dra-matically increases to approach that of
men[108].
Gender-Specific Risk of CVD in Studieson NAFLD and CVD
Several longitudinal studies investigating theassociation
between CVD and NAFLD havereported multivariate analysis models,
whichhave been adjusted for multiple confounders,including sex; as
a result of this, the influence ofgender in the risk of CVD cannot
be evaluatedin such studies (reviewed in [106, 107]). A large
Adv Ther (2017) 34:1291–1326 1305
-
population-based American study (NHANES III)found that NAFLD
assessed with ultrasound,together with male sex, age, race, and
metabolicfactors independently predicted incident CVD[109]. Another
study addressing CHD as a pre-specified outcome found that patients
withNAFLD had a higher 10-year risk for CHD, ascalculated by the
Framingham risk score, thanthe matched control population. This
estimatedrisk was higher in men than in women andmore CVD events
were reported among menthan women at the end of 10 year
follow-up,although this finding was not statistically sig-nificant
[110].
Many cross-sectional studies in which thediagnosis of NAFLD was
based on liver imagingstudies (either ultrasound or CT
scanning)showed an independent association of male sexwith coronary
artery calcifications [111] as wellas significant CHD
[112–115].
Gender Differences in the AssociationBetween NAFLD and CVD
Studies in which the diagnosis of NAFLD wasbased on surrogate
indices, such as otherwiseunexplained raised liver enzymes, found
thatsex modulates the association of NAFLD withincident
CVD/mortality. For example, mostpopulation-based cohort and
meta-analyticstudies reported an independent associationbetween
raised GGT and incident CVD in bothsexes [116]; conversely, a
population-basedcohort study from Germany found thatincreased GGT
was associated with higher riskof all-cause and CVD mortality only
in men butnot in women, and this association was strongerin men who
also had ultrasound scanningfindings compatible with steatosis
[101].Increased ALT has been variably associated withincident CVD
either in both sexes [117, 118] orin men only [119]. A recent study
found thatALT levels independently predicted insulinsensitivity
only in women, suggesting that thisgender-specific association
might explainthe sex difference in the predictive role ofincreased
ALT for CVD [120]. Finally, a recentlarge Korean cross-sectional
study reported thatmen had more prevalent ultrasonographic
fatty
liver disease, carotid plaques, and increasedcarotid
intima-media thickness (IMT) valuesthan women, but ultrasonographic
fatty liverdisease independently predicted subclinicalcarotid
atherosclerosis (IMT and plaques) inwomen only [121].
No gender difference has been reported inthe association between
NAFLD assessed withliver ultrasound and incident CVD/mortality.
Astudy based on a national Danish registryshowed that patients with
a hospital dischargediagnosis of NAFLD had a higher
all-causemortality, including liver and CVD related,which was
similar among sexes [122]. A studyconducted in a community-based
Japanesecohort of 1637 apparently healthy subjectsfound that the
diagnosis of NAFLD based onultrasound findings was a predictor of
CVD inboth men and women [123].
The only study carried out in post-menopausal women found a
significant corre-lation between NAFLD (based on CT
scanningfindings) and prevalence of coronary arterycalcification
(CAC); however, NAFLD was notindependently associated with CAC in
thesepostmenopausal women [124].
In summary, male patients carry anincreased risk of CVD;
moreover, NAFLD seemsto be associated with CVD independently
ofmetabolic factors in both sexes. Few data areavailable in
postmenopausal women and stud-ies should specifically be conducted
to ascertainwhether NAFLD is a specific/independent car-diovascular
risk factor in this population ofpatients.
ROLE OF GENDER, REPRODUCTIVESTATUS, AND AGEIN THE HETEROGENEITY
OF NAFLDPATHOBIOLOGY
Although NAFLD may be found in either genderfrom infancy to old
adulthood, gender andreproductive status modulate the
susceptibilityto development and progression of disease[125].
Indeed age, sex, and fertility exert avariable impact on those
general pathogenicmechanisms which are involved in NAFLD.
1306 Adv Ther (2017) 34:1291–1326
-
Here we will specifically examine how body fatdistribution,
obesity and local hypercorticolism,steatogenesis and lipidomics,
oxidative stressand antioxidant mechanisms, endotoxins,immune
response, and fibrogenesis are affectedby gender and sex hormones
as a result ofreproductive status and age.
Factors Associated with NAFLD areDifferent in Men and in
Women
A pioneering study supporting the notion thatgender-dimorphic
risk factors are associatedwith NAFLD was published in 2000. This
study,by evaluating 199 individuals, found that ele-vated BMI was
an independent predictor of fattyliver in either sex. Glucose area
under the curveand a central-type body fat distribution pre-dicted
fatty liver only in women [126]. Simi-larly, insulin sensitivity
has also been reportedto be strongly associated with
gender-dimor-phic risk factors, i.e., fasting insulin and
leptinlevels (but none of the liver enzymes) in menversus BMI and
ALT in women [120]. Of note,Suzuki et al. demonstrated that the
associationsbetween anthropometric measures (regionaladiposity) and
degree of fibrosis clearly differbetween premenopausal women and
post-menopausal women/men [127].
NAFLD Epidemiologyand Physiopathology are Modulatedby Age at
Menarche and PostmenopausalStatus
In women, a complex interaction includinggenetic polymophisms,
dietary habits, endoge-nous sex hormones, age at menarche,
meno-pausal status, dysmetabolic traits, and HRTmodulates the risk
of developing NAFLD, NASH,and fibrosis [84, 128–130].
Early menarche has been associated withhigher alanine
aminotransferase, C-reactiveprotein, triglyceride levels, BMI,
waist circum-ference, adult diabetes, cardiovascular morbid-ity and
mortality, advanced liver disease, andHCC [131]. A recent Chinese
study conductedin postmenopausal women has identified earlymenarche
as a potential risk factor for NAFLD
later in life; consistently, late menarche protectsfrom NAFLD
[130]. These associations weresignificantly attenuated after
adjustment forcurrent BMI or HOMA-IR, suggesting that obe-sity and
insulin resistance may partly mediatethe association between age at
menarche andNAFLD [130]. The biological mechanism link-ing early
menarche with increased risk ofNAFLD is far from being clearly
elucidated. Ithas been suggested that early maturation maydetermine
a longer duration of positive energybalance and a greater
accumulation of body fat[132]. Consistently, a large
cross-sectional studyamong middle-aged Korean women confirmedthat
the inverse association between age atmenarche and NAFLD was
partially mediated byadiposity [133]. Again, a recent study from
theAmerican CARDIA cohort showed that earlymenarche was associated
with NAFLD and vis-ceral and subcutaneous abdominal ectopic
fatdepots in middle adulthood; these associationswere attenuated
after adjustment for weightgain between young and middle
adulthood[131]. Finally, a Chinese study suggested thatthe presence
of central obesity and MetS, butnot NAFLD, after menopause was
predicted bylonger duration of menstruation and earlymenarche
[134].
Compared to the fertile age, menopauseincreases the risk of
NAFLD and liver fibrosis[135] via long-standing estrogen
deficiencyassociated with ovarian senescence and dys-metabolic
features such as T2D, hypertriglyc-eridemia, and central obesity
[29, 81].Consistently, HRT protects from NAFLD devel-opment [84],
and oophorectomy in youngwomen with endometrial cancer
independentlyincreases the risk of NAFLD together with
thedevelopment of T2D and hypercholesterolemia[136]. These findings
are in agreement with astudy suggesting that, in HCV
infection,increasing severity of fibrosis is associated witha
higher BMI, advanced steatosis, and themenopause and that,
conversely, menopausalwomen receiving HRT exhibit a lower stage
offibrosis [137]. Collectively, these data supportthe notion that
estrogens have antifibrogenicproperties in humans. This
antifibrotic activitymay occur by triggering
anti-inflammatory,antioxidant, and antiapoptotic molecular
Adv Ther (2017) 34:1291–1326 1307
-
pathways [138], which are mimicked by exercisetraining
[139].
Of concern, however, young women intheir reproductive age and
those exposed tofemale synthetic hormones (oral contraceptiveor
HRT) are not completely spared the risk ofdeveloping NAFLD and,
indeed, they tend tohave more severe hepatocyte injury
andinflammation. Notably, despite the possibilityof enhanced
hepatocellular damage, pre-menopausal women have been
consistentlyreported at decreased risk of liver fibrosiscompared to
men and postmenopausalwomen. Moreover, sex hormones exert com-plex
and variable effects on human NAFLD;indeed, the detrimental
pro-inflammatoryimpact may be conveyed by progesterone, butnot
estrogen [97].
Table 3 summarizes the physiological role ofestrogen,
progesterone, and androgens accord-ing to gender, age, reproductive
status, andobesity [140–157].
Obesity and Local Hypercortisolism
Obesity, which is closely linked with NAFLD,mimics
hypercortisolism. It is of interest thatdespite the prevalence of
obesity being higheramong women than men, the former aresomewhat
protected from the associated car-diometabolic consequences;
however, thiswanes after menopause, suggesting a role forestrogens.
Mouse models suggest that sexuallydimorphic expression and activity
of glucocor-ticoid metabolizing enzymes may have a role inthe
differential metabolic responses to obesityin males and females
[158].
Biochemical, genetic, and therapeutic stud-ies have provided
robust evidence for 11b-hy-droxysteroid dehydrogenase type 1
(11b-HSD1)being key in the pathogenesis of NAFLD[159–161]. It is of
interest, therefore, that11b-HSD1 gene expression is regulated in a
tis-sue-specific and sexually dimorphic manner. Inparticular,
intact rats exhibit hepatic 11b-HSD1mRNA levels 18-fold lower in
the female thanthe male [162].
Body Fat Distribution
Regional adiposity displays a typical sexualdimorphism in
humans. Women have a largercapacity to store fat in the
subcutaneous com-partment [163]. Men generally have twice asmuch
visceral fat compared to women for anygiven fat mass value [164].
This is relevant giventhat, compared to subcutaneous adipose
tissuedepots, visceral adipose tissue depots in generaldisplay
greater secretory capacity and a morepro-inflammatory profile
[165]. Moreover, vis-ceral adipose depots release free fatty
acids(FFAs) directly into the portal blood and thuspotentially
overload the liver [166]. Not sur-prisingly, those phenotypes which
occurwhenever, due to hormonal effect, peripheraladiposity is
relatively restricted and visceraladiposity is expanded (i.e., male
obesity andpostmenopausal women) have all been associ-ated with
NASH, and fibrosing NASH[127, 167–169].
Steatogenesis and Lipidomics are Affectedby Sex Hormones
Steatosis will invariably occur as a result of animbalance among
enhanced steatogenesis anddecreased capacity of oxidation of fatty
acids[170]. Moreover, qualitative changes in thehepatic lipidomics
may concur with lipotoxic-ity. Data suggest that all these
mechanisms areunder the control of sex hormones. For
exampleovariectomy in rats is associated with increasedintrahepatic
steatogenesis which occursthrough a decreased synthesis of
peroxisomeproliferator-activated receptor (PPAR), and anincreased
transcription of genes encoding sterolregulatory element-binding
protein 1[(SREBP-1), a nuclear transcription factor andmaster
regulator of the endogenous synthesis ofcholesterol, fatty acids,
triglycerides, and phos-pholipids] and stearoyl coenzyme A
desaturase1 [(SCD1), the rate-limiting enzyme for gener-ating
monounsaturated fatty acids (MUFA)from saturated fatty acids
protects from hepa-tocyte lipotoxicity]; all these effects of
1308 Adv Ther (2017) 34:1291–1326
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Table3
Physiologicalroleof
horm
ones
Men
Wom
enBothsexes
Obesity/type2diabetes
Estradiol
Estradiol
inmen
isessentialfor
modulatinglibido,
erectile
function,and
spermatogenesis
[140]
Astudycond
uctedin
healthymen
suggeststhat
estradiolprotects
from
NAFL
D[141]
End
ogenousestrogensaremaster
regulatorsof
lipid
metabolism
andinhibitinflammation,
vascular
cellgrow
th,and
plaque
progressionin
prem
enopausal
wom
en[142]
The
lossof
estrogenswhich
occurs
postmenopausally
isassociated
withamodestincrease
inLDL
cholesterolw
itheitherno
change
orasm
alldecrease
inHDL
cholesterol.Estrogen
administrationdecreasesLDL
cholesteroland
Lp(a)levelswhile
increasing
triglyceridesandHDL
cholesterollevels,
butthese
effectsaredepend
enton
thedose
androuteof
administration
[143]
Estrogens
improveinflammation
relatedto
metabolicdysfun
ction
(‘‘metaflam
mation’’).
Furtherto
adirect
downregulationof
inflammatorypathways,this
effect
isalso
mediatedby
metabolicam
elioration
[144]
Obesity
isassociated
with
hyperestrogenism
which,inturn,
increasestherisk
ofbreastcancer
inmen
[145]
Progesterone
Progesterone
hasim
portanteffects
inregulating
malefertility
by
affectingtheenergetic
homeostasisof
sperm
[146]
Progesterone
hasamajor
rolein
theovarianandmenstrualcycle;
moreoveritexertsan
immun
o
regulatory
function;regulates
thecontractionof
human
intestinalsm
ooth
musclecells
andthemotility
ofvarious
human
celltypes[147]
Progesterone
isan
independ
ent
predictorof
insulin
resistance
in
girls[148]
Progesterone
hasbeen
potentially
implicated
asatherapeutic
adjunctin
manyclinical
cond
itions
such
astraumatic
braininjury,A
lzheim
er’sdisease,
anddiabeticneuropathy
[147]
Increasing
levelsof
progesterone
have
been
associated
withthe
developm
entof
system
icinsulin
resistance
[149]
Little
isknow
nregardingtherole,if
any,of
serum
progesterone
in
NAFL
D
Adv Ther (2017) 34:1291–1326 1309
-
Table3
continued
Men
Wom
enBothsexes
Obesity/type2diabetes
And
rogens
The
synthesisof
testosterone
iskey
tomalefertility.A
negative
feedback
finelyregulatesthe
secretionof
horm
ones
atthe
levelsof
hypothalam
ic-pituitary–gonadal
axis.C
ongenitalor
acquired
disturbancesof
thisaxiswill
lead
tohypogonadism
andthus
impairmalefertility
[150].
Testosteronehasno
significant
correlationwithNAFL
Din
a
studyfrom
China
[141].
How
ever,itisan
independ
ent
predictorof
insulin
resistance
in
boys
[148]
And
rogens
have
important
biologicalrolesin
youn
gwom
en,
influencing
bone
andmuscle
mass,vascular
health,cognition,
mood,
well-b
eing,and
libido
[151]
How
ever,testosteronedeficiency
inyoun
gwom
enmay
pass
underdiagnosed
becauseof
generally
nonspecific
symptom
s
andinaccuracy
oftestosterone
measurement[152].The
prim
ary
indication
fortheprescription
of
testosterone
forwom
enislossof
libido[153]
Sarcopenia,n
amelythedeclinein
musclemassandstrength
which
occurswithageing,h
asbeen
associated
withadeficiencyin
both
17b-estradioland
testosterone,twosexhorm
ones
which
acto
nsatellitecells.T
hese
remainquiescentthroughout
life
andareactivatedin
response
to
stressfulevents,enablin
gthem
to
guiderepairandregeneration
of
theskeletalmuscle[154]
Obese
men
tend
tobe
hypogonadic
asaresultof
thefunctional
suppressionof
the
hypothalam
ic–p
ituitary–testicular
axis[155].How
ever,w
eightloss
obtained
witheither
alow-calorie
diet
orbariatricsurgeryis
associated
withthenorm
alization
ofsexhorm
onelevelsexhibiting
a
significant
increase
inboun
dand
unboun
dtestosterone
and
gonadotropin
levelsandadecrease
inestradiol[156].A
studyfrom
Japanreported
that
testosterone
levelswereinverselyassociated
withdiabetes
amongmen
butnot
amongwom
en[157]
1310 Adv Ther (2017) 34:1291–1326
-
ovariectomy are prevented by 177b-estradiolreplacement,
indicating a role for estrogens inthe prevention of hepatic fat
accumulation[171]. Consistently, hypoestrogenemia is asso-ciated
with hepatic steatosis through changes ingene expression of
molecules related to fat oxi-dation and lipogenesis; resistance and
endur-ance training prevent this both in rats andhuman models
[172–175]. Moreover, a normalactivity of stearoyl-CoA desaturase
(SCD), therate-limiting enzyme for generating monoun-saturated
fatty acids from saturated fatty acids,protects from hepatocyte
lipotoxicity. Indeed,in mouse models of NAFLD, either
geneticmanipulation or dietary changes that inhibitthe activity of
SCD promote fibrosing NASH viahepatocyte lipotoxicity, despite
inhibiting obe-sity and improving insulin resistance [176,
177].Interestingly, ovarian hormones are alsoinvolved in MUFA
biosynthesis, via SCD1 [178].
Excess 16:0 fatty acids associated with denovo lipogenesis from
high carbohydrate dietinhibits the synthesis of highly
unsaturatedfatty acids; this may potentially account for
theimproved metabolic profile which results fromsupplementing a
hypercaloric diet with pre-formed eicosapentaenoic acid (EPA)
anddocosahexaenoic acid (DHA) [179]. For exam-ple, findings from a
genetically engineeredNASH mouse model fed a Western diet haveshown
that dietary DHA was superior to EPA inattenuating Western
diet-induced hyperlipi-demia and hepatic injury and at reversing
thosedeleterious metabolic and histological effectsinduced in the
liver by a Western diet [180].Interestingly, human (women using the
con-traceptive pill or HRT and transsexual subjects)and
experimental data in rats consistentlyindicate that sex hormones
act to modifyplasma and tissue n-3 PUFA content, possibly
byaltering the expression of desaturase and elon-gase enzymes in
the liver [181]. Collectively,these findings suggest that enzyme
activitieswhich are key in the development of a poten-tially
hepatotoxic lipidomic signature are criti-cally controlled by sex
hormones. Finally, it isof clinical importance that the
therapeuticactivity of PPAR-a agonists in obesity and fattyacid
oxidation is modulated by sex and estro-gens [182].
Oxidative Stress and AntioxidantMechanisms
Reactive oxygen species (ROS) result from theoxidation of fatty
acids within mitochondriaand peroxisomes. The antioxidant
defenseswhich physiologically constrain oxidative stressare
hindered by nutritional deficiencies orchanges in the intestinal
microbiome that limitavailability of choline [183]; by aging and
thecontent of cysteine in diet, which, in turn, willaffect the
intrahepatic synthesis of glutathione[184]; and by sex and
menopause which bothaffect the normal metabolism of choline
[185].
Endotoxin
Quali-quantitative changes in intestinal micro-biota
(dysbiosis), which are often associatedwith dietary indiscretions,
have consistentlybeen associated with increased gut
permeabilitywhich could lead to increased translocation ofbacterial
products from the intestinal lumeninto the portal circulation,
thereby triggeringchronic inflammation [170]. It this context, it
isrelevant that in an experimental model of liverfailure due to
endotoxemia after hepatectomy,sexually mature female rats are more
exposedthan males to endotoxin-induced liver injuryand that
ovariectomy abrogates this sexualdimorphism [186]. Whether this
also applies tohuman NAFLD, however, remains to be proven.
Interindividual Variation in ImmuneResponses is Another Key
Liver DiseaseModifier in NAFLD
Whether metabolic inflammation is a gen-der-dimorphic phenomenon
has not beenexplored in a systematic and organized manner.Obesity,
however, will typically exhibit changesin the innate and adaptive
immune mecha-nisms [187]. However, how mechanisticallysuch
obesity-related dysregulation of immunedefenses will impact on the
pathogenesis ofNASH is not fully elucidated. Experimental
dataobtained in the ob/ob mouse model suggest arole for natural
killer T cells (NKT cells) whichmay at least partly account for
the
Adv Ther (2017) 34:1291–1326 1311
-
interindividual variation in immune responsesbeing a key
modifier in the development andprogression of NAFLD [125]. In this
respect, itshould be highlighted that sex is a majordeterminant in
the immune response. Sup-porting this notion, one study in young
chil-dren reported that immune responses tovaccines were
consistently higher or equivalentin girls compared with boys
[188].
Liver Fibrosis
Liver fibrosis is the end-stage result of variousliver injuries.
In recent times, importance hasbeen given to the Hedgehog signaling
pathwayon the grounds that activation of this pathwaywill stimulate
the proliferation and differentia-tion of hepatic stellate cells
(HSCs) as myofi-broblasts (MF-HSCs), and, conversely,inhibiting
Hedgehog activity in myofibroblastsderived from HSCs causes them to
revert to amore quiescent (namely less fibrogenic) phe-notype
[125]. Accordingly, Hedgehog ligandsand other factors that control
fate decisions inHSCs are critical determinants of the develop-ment
of cirrhosis due to various causes as well ofthe course of NASH
[125]. For example, hepaticexpression of Hedgehog ligands and
Hedgehogpathway activity progressively increase fromsimple
steatosis, to NASH, and reach highestlevels in NASH-cirrhosis
[189]. Of major signif-icance to the pathogenesis of NAFLD,
theHedgehog pathway is strongly regulated bylipids [190], and
conversely, Hedgehog signal-ing is a master regulator of body fat
distributionand glucose metabolism [191, 192]. Thesefindings
suggest that interindividual variationin Hedgehog signaling might
contribute tovariability in both hepatic and extrahepaticoutcomes
of the metabolic syndrome [125].
Experimental overexpression of Hedgehogligand in hepatocytes is
able to induce a fibro-genic liver response and to promote
hepato-carcinogenesis in a transgenic mouse model[193]. At least in
part by modulating interme-diary metabolism [194, 195], Hedgehog
alsointeracts with pathways which regulate growthand
differentiation [194, 196–198], such asWnt/b-catenin signaling,
which are of potential
significance for the development of hepatocel-lular carcinoma
[199].
Treatment with compounds, e.g., vitamin E,that suppress Hedgehog
ligand production andreduce the hepatic accumulation of
Hedge-hog-responsive myofibroblasts has proven ben-eficial in human
NASH [200].
Further studies are necessary to establishwhether and to what
extent sex hormonesaffect Hedgehog signaling and how manipula-tion
of cellular energy homeostasis might beexploited to prevent and
manage fibrosingNASH, cirrhosis, and HCC in individuals
withNAFLD.
CAN GENDER DIMORPHISMOF NAFLD BE EXPLOITEDFOR THERAPEUTIC
PURPOSES?
In principle, sex differences found in NAFLDmay be accounted for
by the effects of sexchromosomes; sex hormones; and by differ-ences
in dietary and lifestyle habits [201, 202]. Abetter understanding
of the physiopathologicalpeculiarities of NAFLD in women may
con-tribute to developing tailored therapeuticinterventions [203].
Accordingly, the roles ofestrogen and HRT, the metabolism of
choline,and the effect of weight reduction and exercis-ing in women
are discussed in detail hereafter.
Estrogens
As detailed in Table 3, estrogens exert severalbeneficial
metabolic effects. Experimental stud-ies suggest that estrogens
promote the accu-mulation of peripheral gluteofemoralsubcutaneous
adipose tissue and, within theliver, promote FFA beta-oxidation and
preventthe accumulation of triglycerides; moreover,they regulate
energy homeostasis, enhanceinsulin sensitivity, and exert a
protective roleon the function of pancreatic beta-cells
[201].Finally, estrogens seem to have antisteatotic,antioxidant,
and antifibrogenic properties inthe liver [204, 205]. Estrogens may
protect fromliver steatosis and fibrosis in female mice
viaupregulation of miRNA-125b and miRNA-29,
1312 Adv Ther (2017) 34:1291–1326
-
respectively [206, 207]. A recent experimentalstudy showed that
the estrogen/estrogenreceptor alpha signaling plays essential roles
inROS detoxification and in the reduction ofoxidative damage in the
liver via partneringwith hepatic PPARG coactivator 1 alpha,
thushalting the transition from simple steatosis tosteatohepatitis
[205]. Estrogens are also knownto inhibit stellate cell activation
and fibrogene-sis in experimental models [204]. Of note, astudy
showed that the natural estrogen17b-estradiol prevents deoxycholic
acid-in-duced hepatocellular damage in several celllines. This
hepatoprotective effect of estrogenwas sustained by mechanisms
which wereunlikely to be mediated by nuclear estrogenreceptor alpha
[208]. Interestingly, it hasrecently been demonstrated that a
non-nuclearestrogen receptor plays a key role in reducinghepatic
steatosis in female mice [209]. Similarly,estrogen deficiency leads
to fat redistributiontoward visceral fat accumulation and its
inher-ently unfavorable metabolic derangements, andis thus able to
induce the development andprogression of NAFLD/NASH both in mice
andhumans. Of note, both aromatase knockoutmice, which are unable
to synthesize endoge-nous estrogen, and estrogen receptor
alphaknockout mice develop hepatic steatosis[210–212]. Patients
with breast cancer treatedwith tamoxifen, a potent estrogen
antagonist,develop progressive liver steatosis and NASH[213].
Surgical and physiological menopausalstatus have been invariably
associated withexcess risk of NAFLD progression and liverfibrosis,
and duration of estrogen deficiency hasbeen directly related to
increased fibrosis risk inpostmenopausal women with NAFLD[95, 96,
98, 136].
Hormonal Replacement Therapy
Despite the above premises, the role of HRT inreverting the
metabolic alterations associatedwith low levels of estrogens is a
matter of dis-pute. In animal models, both estrogen andraloxifene,
a second-generation selective estro-gen receptor modulator, have
improvedinflammation and ballooning so halting the
progression of liver fibrosis in diet-inducedNASH in female
ovariectomized mice [30, 214].However, the theoretical benefits of
HRT in liverdisease remain to be proven in humans. Aseminal
randomized placebo-controlled studysuggested that HRT containing
low-dose estra-diol and norethisterone was able to reduce
liverenzyme concentrations in women with T2D,potentially through
the reduction of accumu-lation of fat in the liver [45].
Accordingly, anorth American study using data of theNHANES III
survey showed that post-menopausal women who received HRT had
asignificantly lower risk of NAFLD than post-menopausal women who
did not (OR 0.69, 95%CI 0.48–0.99) [215]. However, whether
HRTreduces the risk of NASH and/or fibrosis amongpostmenopausal
women remains uncertain.Two studies showed no, or borderline,
benefi-cial effects of HRT on fibrosis among post-menopausal women
with NAFLD [95, 96].Worryingly, a recent study reported that
syn-thetic hormone use was associated with moresevere
hepatocellular injury and lobularinflammation. Further analysis
showed thatprogesterone, but not estrogen use, was associ-ated with
worse liver histological lesions, sug-gesting a multifaceted impact
of sex hormoneson NASH features [97].
Choline
Several lines of evidence support a key role ofcholine as an
essential nutrient and cellularcomponent. Choline is the major
source ofmethyl groups in the diet and is a precursor
ofphosphatidylcholine, which is an importantcomponent of cell
membranes and VLDL,required for the export of lipids from the
liverinto the bloodstream. Thus, depletion of cholineinhibits
hepatic triglyceride export and inducesfatty liver in both
experimental models andhumans [185, 203, 216, 217]. Of note,
post-menopausal women are more prone than pre-menopausal women and
men to develop NAFLDas a consequence of choline deficiency[128,
185, 217], and decreased dietary cholineintake has been
significantly associated withincreased fibrosis in postmenopausal
women
Adv Ther (2017) 34:1291–1326 1313
-
with NAFLD [218]. Indeed, menopausal statusdetermines a
differential susceptibility to cholinedeficiency arising from the
estrogen-inducibleexpression and activity of
phos-phatidylethanolamine-N-methyltransferase(PEMT), a key enzyme
in de novo cholinebiosynthetic pathway. Following menopause,the
endogenous supply of choline decreases as aresult of estrogen
deficiency; consequently, thedietary requirement of choline is
increased[185, 203, 216, 217]. Consistently, choline
sup-plementation has been reported to improve orrevert liver
steatosis in patients receivinglong-term total parenteral nutrition
[219]. How-ever, no interventional studies have addressedwhether
choline supplementation is able to pre-vent NAFLD or reduce NAFLD
progression; more-over, future studies investigating the role
ofpreventive or therapeutic choline supplementa-tion in
postmenopausal women are eagerlyawaited.
Weight Reduction and Exercise
Lifestyle changes, i.e., physical activity and bal-anced diet,
are the milestone of intervention forNAFLD treatment. In general,
weight lossinduced by lifestyle changes improves IR andfeatures of
the MetS, including NAFLD. Of note, amodest weight loss of as
little as 2–3 kg is associ-ated with NAFLD reversal [39], and
weight loss ofgreater than 7–10% significantly improves
his-tological features of NASH, including fibrosis[220]. However,
significant weight reductionachieved through dietary restrictions
results innegative effects on lean muscle and bone mass
inpostmenopausal women. Therefore, whileweight reduction in
postmenopausal womenwith metabolic abnormalities and risk factors
forNAFLD should be strongly recommended, spe-cial attention should
be paid to how weight loss isobtained in older women to prevent the
wors-ening of loss of lean mass [139, 203]. An inte-grated approach
consisting of dietary changesalong with regular exercise is
mandatory to pre-vent the untoward effect of losing lean mass.Both
resistance training and aerobic exercise areeffective in preventing
muscle and bone lossduring weight loss [203], and equally reduce
liver
fat content [221, 222]. Postmenopausal womenwith higher levels
of physical activity seem tohave lower total body and visceral fat
and to beless likely to gain fat mass during menopause[139, 223].
However, only few studies havespecifically assessed the role of
physical activityin NAFLD prevention/reversal in post-menopausal
women. Data have shown thatexercise training effectively reduces
liverenzymes in overweight postmenopausal women,probably as a
reflection of liver fat content [224],and aerobic physical activity
reduces cardiovas-cular risk factors in postmenopausal women
withNAFLD [225]. Further studies are needed todefine the ideal
structure and duration of exer-cise-based interventions in
postmenopausalwomen with NAFLD or at risk of developing it.
In summary, there are no codified therapeuticinterventions
approved for tackling NAFLD inwomen. Given the theoretical
beneficial meta-bolic and hepatic effects of estrogens, it
isintriguing to speculate that HRT might possiblyplay a role in the
prevention and treatment ofmetabolic alterations associated with
meno-pause, including NAFLD. However, studies inhumans are lacking
and the potential metabolicbenefits should be weighed, in clinical
practice,against the detrimental cardiovascular and neo-plastic
risk associated with long-term HRT[226, 227]. Moreover, the
multifaceted and vari-able impact of different sex hormones in
NAFLDshould be carefully considered. Dietary changesassociated with
either aerobic or resistancephysical exercise should be considered
as themilestone of treatment of NAFLD. Future studieswill have to
evaluate the effects on NAFLD pre-vention/treatment of
supplementing choline toa balanced diet in postmenopausal
women.Finally, the physiopathological peculiarities ofNAFLD in
women and the gender-based differ-ences in the kinetics and
dynamics of drugs andxenobiotics should be taken into account
whendeveloping new treatment strategies andproposing interventional
trials for NAFLD.
CONCLUSION
Consistent with the notion that NAFLD andNASH are strongly
linked with hormonal
1314 Adv Ther (2017) 34:1291–1326
-
influences [228], this narrative review article wasdriven by the
hypothesis that what we called the‘‘sexualdimorphism’’ ofNAFLD
might be useful inidentifying clues of pathogenic significance
andproviding hints for prevention and treatment ofNAFLD. On these
grounds, a systematic researchof the literature was conducted. What
we foundwas that not only are men at an increased risk ofdeveloping
NAFLD (Fig. 1) but also significantage-related changes in NAFLD
epidemiology inwomen may potentially bear
physiopathological,clinical, and therapeutic significance.
NAFLDepidemiology and physiopathology are modu-lated by age at
menarche and postmenopausalstatus (Fig. 2). It would be expected
that earlymenarche, definitely associated with estrogen
activation, would produce protection against therisk of NAFLD.
Nevertheless, it has been suggestedthat early menarche may confer
an increased riskof NAFLD in adulthood, excess adiposity beingthe
primary culprit of this association. Fertile agemay be associated
with more severe hepatocyteinjury and inflammation, but also with
adecreased risk of liver fibrosis compared to menandpostmenopausal
status.Ovariansenescence isstrongly associated with severe
steatosis andfibrosing NASH which may occur in post-menopausal
women. Estrogen deficiency isdeemedtobe responsible for these
findings via thedevelopment of postmenopausal metabolic syn-drome.
Estrogen supplementation may at leasttheoretically protect from
NAFLD development
NAFLD RISK HIGHLOW
PUTATIVE MECHANISMSNEMNEMOW
GLUTEOFEMORAL Distribu�on of adipose �ssue VISCERAL
KETONE BODY Fa�y acid par��oning VLDL-TAG
+ Browning of WAT -
Fig. 1 Physiopathological grounds accounting for male sexas a
strong predictor of NAFLD. Male gender andmenopausal status have
been associated with the risk ofNAFLD independently of age and
metabolic factors incross-sectional studies. On the basis of human
studies andextrapolation of notions from animal studies, it can
bespeculated that female sex is protected from dysmetabolismthanks
to young individuals’ ability to partition fatty acidstowards
ketone body production rather than VLDL-TAG
[23], and to sex-specific browning of white adipose tissuewhich
contributes in protecting female mice from exper-imental NAFLD
associated with methionine cholinedeficient diet [24]. However,
after menopause womendisplay a similar or even higher prevalence of
NAFLDcompared to men, supporting a protective effect ofestrogens.
Finally, risk factors associated with NAFLDdevelopment are
different in men compared to women.TAG triacylglycerols, WAT white
adipose tissue
Adv Ther (2017) 34:1291–1326 1315
-
and progression, as suggested by some studiesexploring the
effect of HRT on postmenopausalwomen, but the variable impact of
different sexhormones in NAFLD (i.e., the pro-inflammatoryeffect of
progesterone) should be carefully takeninto account when proposing
treatment withsynthetic hormones.
Taken collectively, these data may generateinnovative hypotheses
to be tested in appro-priate clinical and experimental studies
onNAFLD physiopathology and treatment.
ACKNOWLEDGEMENTS
No funding or sponsorship was received for thisstudy or
publication of this article.
All named authors meet the InternationalCommittee of Medical
Journal Editors (ICMJE)criteria for authorship for this manuscript,
takeresponsibility for the integrity of the work as awhole, and
have given final approval for theversion to be published.
Stefano Ballestri, Fabio Nascimbeni, andAmedeo Lonardo conceived
the idea of thisarticle and wrote its first draft. All the
authorshave read, edited, and approved the variousversions of this
article.
Disclosures. Stefano Ballestri and EnricaBaldelli have nothing
to disclose. FabioNascimbeni is involved as a researcher in
the‘‘Phase 3, Double Blind, Randomized,Long-Term,
Placebo-controlled, Multicenter
STEATOFIBROSIS
Fig. 2 Hormonal changes are a major determinant ofprogressive
NAFLD in human menopause. NAFLDepidemiology and physiopathology are
modulated by ageat menarche and postmenopausal status. For example,
earlymenarche may confer an increased risk of NAFLD inadulthood
partly mediated by excess adiposity
[130, 131, 133]. Moreover, ovarian senescence, via
estrogendeficiency, may eventually be conducive to both
massiveliver steatosis and its fibrotic evolution via
dysmetabolictraits including T2D, hypertriglyceridemia, and
visceralobesity which are often found postmenopausally[29, 81,
135]
1316 Adv Ther (2017) 34:1291–1326
-
study evaluating the Safety and Efficacy ofObethicolic Acid in
Subjects with NASH’’ (Eu-draCT 2015-002560-16). Alessandra Marrazzo
isinvolved as a researcher in the ‘‘Phase 3, DoubleBlind,
Randomized, Long-Term, Placebo-con-trolled, Multicenter study
evaluating the Safetyand Efficacy of Obethicolic Acid in Subjects
withNASH’’ (EudraCT 2015-002560-16). AmedeoLonardo is involved as a
researcher in the ‘‘Phase3, Double Blind, Randomized,
Long-Term,Placebo-controlled, Multicenter study evaluatingthe
Safety and Efficacy of ObethicolicAcid in Subjects with NASH’’
(EudraCT2015-002560-16). Dante Romagnoli serves as aconsultant for
AbbVie.
Compliance with Ethics Guidelines. Thisarticle is based on
previously conducted studiesand does not involve any new studies of
humanor animal subjects performed by any of theauthors.
Data Availability. All data generated oranalyzed during this
study are included in thispublished article.
Open Access. This article is distributedunder the terms of the
Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense
(http://creativecommons.org/licenses/by-nc/4.0/), which permits any
noncommer-cial use, distribution, and reproduction in anymedium,
provided you give appropriate creditto the original author(s) and
the source, providea link to the Creative Commons license,
andindicate if changes were made.
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