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Current Molecular Medicine 2020, 20, 1-12 1
REVIEW ARTICLE
1566-5240/20 $65.00+ .00 © 2020 Bentham Science Publishers
Alcohol Consumption and Risk of Uterine Fibroids
Hajra Takala1, Qiwei Yang1,*, Ahmed M. Abd El Razek2, Mohamed Ali1,3 and Ayman
Al-Hendy1
1Department of Obstetrics and Gynecology, College of Medicine, University of Illinois at Chicago, Chicago, IL
60612, USA; 2Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois
at Chicago, Chicago, IL 60607, USA; 3Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams
University, Cairo, Egypt
A R T I C L E H I S T O R Y
Received: June 26, 2019
Revised: September 23, 2019
Accepted: September 27, 2019
DOI:
10.2174/1566524019666191014170912
Abstract: Lifestyle factors, such as alcohol intake, have placed a substantial burden on
public health. Alcohol consumption is increasing globally due to several factors including
easy accessibility of this addictive substance besides its legal status and social
acceptability. In the US, alcohol is the third leading preventable cause of death (after
tobacco, poor diet and physical inactivity) with an estimated 88,000 people dying from
alcohol-related causes annually, representing 1 in 10 deaths among working adults.
Furthermore, the economic burden of excess drinking costs the US around $249 billion
($191.1 billion related to binge drinking). Although men likely drink more than women do,
women are at much higher risk for alcohol-related problems. Alcohol use is also
considered to be one of the most common non-communicable diseases, which affects
reproductive health. This review article summarizes the current knowledge about
alcohol-related pathogenesis of uterine fibroids (UFs) and highlights the molecular
mechanisms that contribute to the development of UFs in response to alcohol
consumption. Additionally, the effect of alcohol on the levels of various factors that are
involved in UFs pathogenesis, such as steroid hormones, growth factors and cytokines,
are summarized in this review. Animal studies of deleterious alcohol effect and future
directions are discussed as well.
Keywords: Alcohol, UFs, epidemiological studies, steroid hormones, growth factors, cytokines, reproductive
diseases, metabolism.
1. INTRODUCTION
Uterine Fibroids (UFs), also known as fibroids or
uterine leiomyoma, are one of the most common
diseases that affects women’s reproductive health. It
affects nearly 70% of all reproductive-age women [1].
UFs are hard masses of monoclonal smooth muscle
embedded in the myometrium [2]. UFs impart a harmful
impact on women's health, including pain, heavy
menstrual bleeding, infertility, abortion and preterm
labor [3]. Symptomatic UFs may require medical or
surgical intervention and increased medical utilization.
In the U.S., UFs account for nearly 30% of all
hysterectomies among women ages 18–44 years,
which cause tremendous health-care expenses [4].
UFs tumors were estimated to cost the US $5.9-34.4
billion annually [5]. Additionally, a large proportion of
UFs is diagnosed incidentally in the absence of
symptoms, during a routine pelvic exam or screening
for another medical condition. Incidence of UFs is 2–3
times greater among black women compared to white
women. Black women develop UFs earlier and present
*Address correspondence to this author at the department of
Obstetrics and Gynecology, University of Illinois at Chicago, 820
South Wood Street, Chicago, IL 60612, USA; Tel: +1 312 996 5689;
Fax: +1 312 996 4238; E-ma il: qiwei@uic.edu
symptoms that are more aggressive. Molecular
mechanisms and factors that influence UFs prevalence
are not yet fully elucidated [6, 7]. The development of
UFs is complex and affected by several factors such as
hormones, cytokines and growth factors, epigenetic
abnormalities and genetic factors [1, 7-11]. UFs growth
could be affected by steroid hormones and other
hormones, such as growth hormone and prolactin. In
addition, many cytokines, such as insulin-like growth
factor 1 (IGF-1), epidermal growth factor (EGF), and
platelet-derived growth factor (PDGF) have been
shown to associate with the accelerated growth of UFs
[12]. Dietary factors, such as vitamin D deficiency
increased the risk for developing UFs, it has been
directly associated with the volume of UFs among
different ethnic groups [13, 14]. In addition, other risk
factors, including alcohol consumption, which is
associated with UF development, have been reported
[15].
Abnormalities in alcohol metabolism may affect the
vulnerability of individuals to risk for alcohol related
problems [16]. As we will discuss later in this review
article, many factors, rather than the amount of alcohol,
were engaged in pathogenesis of alcohol induced
reproductive problems, including genetic factors
manifested by the variations in the enzymes that break
down alcohol to acetaldehyde and then to acetic acid.
2 Current Molecular Medicine, 2020, Vol. 20, No. 00 Takala et al.
In addition, alcohol consumption results in oxidative
stress, epigenetic changes, and changes in levels of
hormones, cytokines and growth factors leading to
reproductive problems [17, 18]. However, to date,
investigation of the risk of alcohol consumption in
human UFs is lacking.
2. ALCOHOL AND FEMALE REPRODUCTION
Several studies have explored the effect of alcohol
on mammalian female puberty along with female
reproductive maturation [19, 20, 21]. Reproductive
maturational events are sensitive to environmental
factors throughout various life stages, including
prenatal exposures to alcohol [20]. Sliwowska et al
tested the adverse effect of prenatal alcohol exposure
(PAE) and found that PAE inhibited the expected
increase in estradiol (E2) levels with age and delayed
maturational increases of progesterone (P4) levels [20].
Moreover, prepubertal rats that were fed with alcohol
showed a marked ovarian failure compared with
animals that did not receive alcohol but were fed the
same number of total calories for the same time period
[22, 23]. Other experiments on prepubertal female rats
demonstrated that hormonal changes, in response to
either short term or chronic alcohol exposure, are
responsible for delayed puberty [24, 25]. These
hormones are involved in female pubertal process [26,
27]. Dees et al demonstrated detrimental effects of
alcohol on the activation of hormone secretion (LH, E2,
growth hormone, and insulin- like growth factor-1) that
accompanies female puberty [28]. Interestingly, alcohol
did not affect age at menarche [29]. Alcohol–induced
reproductive disruptions, such as abnormal female
cycling have also been investigated in several other
animal models [30-32].
The postulated mechanisms underlying alcohol’s
disruption of female cycle in rat models include a
temporary elevation of E2 [23], which was similar to
human studies [33], as well as temporary increase in
testosterone level, which is a well–known suppressor of
the hypothalamic–pituitary unit [34]. Therefore, an
increase in testosterone could disturb normal female
cycling and decrease IGF–1 level in the bloodstream.
IGF–1 evokes LHRH (Luteinizing hormone-releasing
hormone) release in female rats [35, 36]. Moreover, in
acute alcohol studies, the ability of IGF–1 to increase
LH was blocked by alcohol [37].
Although investigation on the effects of alcohol in
the older female rat (menopausal) model is limited, a
study of rats, whose ovaries had been surgically
removed to mimic the human menopausal state,
demonstrated that heavy chronic alcohol exposure was
able to increase estrogen levels [38].
In human, despite the abundance of studies on fetal
alcohol spectrum disorder, few studies have been
performed to reveal the adverse effects of PAE on the
reproductive system. Robe et al showed that maternal
heavy drinking delayed onset of daughters’
menstruation [39]. Carter et al found that PAE elevated
testosterone concentrations and decreased tissue
responsiveness to testosterone in both males and
females [40]. Nevertheless, up to date, there is
insufficient information on the effect of in utero alcohol
exposure on the reproduction of female offspring.
Furthermore, studies on the physiological effects on
human females in pubertal ages are limited. It has
been hypothesized that during puberty, occurring of the
rapid hormonal changes makes females especially
vulnerable to the deleterious effects of alcohol
exposure. Block et al conducted a study showing that
estrogen levels were depressed among adolescent
girls after drinking moderately [41].
In premenopausal women, increases in total
estrogen levels and amount of bioavailable estrogens
are associated with alcohol consumption [42]. A
randomized clinical study conducted by Sorkola et al
showed a differential hormonal effect of acute alcohol
intake with increased E2 levels and decreased P4
levels in premenopausal women who use oral
contraceptives. Among subjects not using oral
contraceptives, intake of alcohol decreased the levels
of P4 without changing the E2 levels [43].
Concordant with animal models, studies of alcohol
effects on postmenopausal women showed that acute
alcohol exposure results in a temporary increase in E2
levels in menopausal women who use hormone
replacement therapy (HRT), while interestingly alcohol
exposure did not have any effects on E2 levels in
women who were not receiving HRT [44, 45]. Patterns
of alcohol use was also studied in postmenopausal
women and E2 levels were found to be increased in
normal postmenopausal women who consume
alcoholic beverages moderately, and to be even further
increased in alcoholic postmenopausal women with
cirrhosis [46]. Collectively, Alcohol consumption can
affect women health with adverse fertility
consequences. Alcohol-induced disruption of female
fertility could be due to direct effect in which alcohol
markedly disrupts normal menstrual cycles that impairs
the reproductive function and lead to early menopause,
or indirectly via effects on other health problems, such
as liver disease and malnutrition [33, 47, 48]. Wilsnack
et al showed that drinking alcohol at different levels
exhibits many reproductive dysfunctions and various
menstrual problems [49].
3. EPIDEMIOLOGICAL STUDIES ON UTERINE
FIBROIDS ASSOCIATED WITH ALCOHOL
INTAKE
Epidemiological applications have cleared limited
information about the relationship between UFs and
alcohol (Table 1). Nurses’ Health Study II (NHSII) is a
prospective study of premenopausal women
(predominantly Caucasian population). The
investigation of the risk factors for chronic diseases in
women was the aim of this study. A part of the NHSII
study was an application, which was conducted to
determine the variation in the incidence of UFs in
women with no history of UFs. The study showed a
positive association of current alcohol consumption
Alcohol Consumption and Risk of Uterine Fibroids Current Molecular Medicine, 2020, Vol. 20, No. 00 3
Table 1. Summary of epidemiological studies of UFs in relation to alcohol use
Alcohol
intake!
Study
Design!
Site !
Time of Study!
Cases!
Age
(yrs.)!
Outcome !
Public-
ation
Year!
Authors!
Refe-
rences!
Current
alcohol
intake !
Prospectiv
e cohort!
USA!
September 1989 -
May 1993
(Nurses' Health
Study II)!
US black and
white women with
UFs (diagnosed ≤
2 years and
confirmed by
hysterect omy, US,
or PE)!
25-44!
Positive
association of
current alcohol
intake with UFs
risk!
1997!
Marshall
et al !
[15]!
Total
daily
average
alcohol
intake !
Case-
control!
Italy!
1986 - 1997!
Women with UF
(histologically
confirmed)!
21- <55 !
No association
between
alcohol intake
and UFs !
1999 !
Chiaffari
no et al!
[58]!
Current
alcohol
intake,
intake at
age 30 !
Case-
control!
USA!
Initial enrollment
and screening
1996-1999, The
first follow-up in
2001-2002, and
the final follow-up,
in 2004-2005
(NIEHS Uterine
Fibroid study)!
US black and
white Women with
UF (confirmed by
TVUS)!
35- 49!
Current alcohol
intake in white
women was
associated with
an increase in
the risk of UFs
as compared
with non-
drinkers, and
was also a
strongest factor
for small UFs,
and alcohol
intake at age
30 was most
strongly related
to large tumors!
2004!
D'Aloisi
o et al!
[56]!
Never,
former,
current
drinkers!
Prospectiv
e cohort!
USA!
1997 - 2001!
!
US black women
with UF (confirmed
by US or
hysterect omy)!
21- 69!
Positive
association of
UFs risk with
the years of
alcohol intake
and current
alcohol intake,
particularly
beer!
2004!
Wise et
al!
[51]!
None, <
20 g,
≥20
g/day!
Prospectiv
e cohort!
USA!
Baseline
questionnaire in
1995-1996.
Confirmation of
the diagnosis ;
1991 - 2006
(California
Teachers Study)!
Non-Latina White,
African American,
Latina,
Asian/Pacific
Islander, or other
(including mixed or
unknown race)
Californian women
with UF (confirmed
surgically)!
25–84!
Alcohol
consumption
associated with
increased risk
of UFs!
2009!
Temple
man et
al!
[53]!
Never,
ever;
total
alcohol
intake
g/day!
Case-
control!
Japa
n!
October 2003 -
March 2 006!
Japanese women
with UFs
(confirmed by
TVUS), self-
reported UFs
(women who had
undergone
hysterect omy)!
23-56!
Higher
prevalence of
UFs with
higher alcohol
intake!
2009!
Nagata
et al!
[54]!
Never,
ever!
Case-
control!
Chin
a!
October 2009 -
April 2011!
Women with UFs
(confirmed by US
or hysterectomy)!
≥18 - <
56!
No association
between U Fs
and alcohol
intake!
2013!
He et al !
[57]!
Abbreviat ions: NI EHS: National Institute of Envir onmental Health Sciences, US: Ultrasound, TVUS: Transvaginal Ultrasoun d; PE: pelvic examinati on.!
4 Current Molecular Medicine, 2020, Vol. 20, No. 00 Takala et al.
with UF risk. However, the authors did not report the
estimates of the association between alcohol intake
and UFs risk [15, 50]. The Black Women Health Study
(BWHS) is the largest follow-up study of the African-
American women health conducted from all parts of the
United States. The purpose of the study was to identify
and evaluate causes and preventives of serious
illnesses in African-American women, UFs was among
the studied diseases. Notably, BWHS is considered the
first epidemiological study that analyzed separately the
role of different types of alcoholic beverages in UFs
risk. The study concluded that UFs risk in black women
was positively associated with the years of alcohol
intake and current alcohol consumption, particularly
beer. A possible explanation is that beer exerts a
different effect than other types of alcohol on hormone-
dependent neoplasms [51].
Prospectively, California Teachers Study was
conducted on women of different age groups, to
describe reproductive and lifestyle correlates of
surgically confirmed UFs [52, 53]. Over 133,000 female
teachers and school administrators were involved
through the California State Teachers Retirement
System. Participants reported no prior history of UFs.
Results showed that drinking 20 g or more of alcohol
per day significantly associated with increased risk for
a surgical diagnosis of UFs. Diary intake was classified
as none, less than 20 g, 20 g or more, or unknown
based on previous findings of this cohort) [53]. Another
cross-section study further supported this causal risk
factor in UFs on premenopausal Japanese women
which found that mean alcohol intake was statistically
significant and higher among women with UFs than
those without UFs. In this study, however, there was no
significant association between the intake of other
dietary components (fats, soya isoflavones, or dietary
fiber) and UFs [54]. Women who ever drank alcoholic
beverages were also found to be more relatively at risk
of having UFs [55].
Furthermore, the involvement of alcohol intake in
the initiation or early growth of UFs was demonstrated
in a study that has also shown a variation in the
association of alcohol intake with UFs by race and
tumor size. 1146 premenopausal black or white women
were included in the study. The study concluded that
current alcohol intake in white women was associated
with an increase in the risk of UFs as compared with
non-drinkers, odds ratio with current drinking was
strongest for small UFs, and alcohol intake at age 30
was most strongly related to large tumors. Interestingly,
the study did not find an association of alcohol intake
with UFs in black women, however, the patterns for
current and past drinking with UF size were generally
similar to those for white women [56]. Despite evidence
from epidemiological studies of the potential risk of
alcohol for developing UFs, other epidemiological
studies contradicted this risk [57, 58]. One study
analyzed the relation between selected dietary
indicators including alcohol and the risk of UFs in
Italian women of age less than 55-years. The study did
not find any association between alcohol intake and
UFs. However, the authors of this study explained the
lack of association between alcohol and UFs by the
fact that wine was accounted for >90% of the alcohol
consumed [58]. It is possible that wine has no effect on
hormone-dependent neoplasms. Further experimental
studies are warranted to extend this study.
4. THE MECHANISMS OF ALCOHOL-RELATED
PATHOGENESIS OF UTERINE FIBROIDS
4.1. Alcohol and Steroid Hormones
Experimental and clinical studies support the
important role of steroidal hormones, estrogen and
progesterone, in the promotion of UFs [51, 59]. This
explains the growth of UFs during the reproductive
years, and their regression in the presence of low
levels of estrogen, such as following menopause [60],
or during the use of anti-hormonal therapies such as
gonadotropin-releasing hormone (GnRH) agonists.
Furthermore, this might explain the higher risk of UFs
in nulliparous women who might be subject to a higher
frequency of anovulatory cycles (greater estrogen
exposure) and obese women with greater
aromatization of androgens to estrone in the adipose
tissue. Increased growth of UFs among women taking
tamoxifen or receiving transdermal or injectable
estrogen replacement therapy further supports the
implication of the estrogens. Estrogen levels are
reported to be affected by parity, drugs, BMI. In
addition, dietary factors including alcohol were also
shown to affect estrogen levels. An investigational
study has demonstrated an increase in total estrogen
levels and amount of bioavailable estrogens with
alcohol consumption in premenopausal women.
Furthermore, this study has found alcohol intake
differentially affects both serum and urinary estrogens
levels at different points of the menstrual cycle [42].
Other studies supported the alcohol’s effect on steroid
hormones and showed associations between alcohol
intake and high levels of plasma or urinary estradiol,
estrone, and androstenedione [61, 62]. Regardless of
women’s age, alcohol consumption increases estradiol
levels in both premenopausal and postmenopausal
women [63, 64].
4.2. Alcohol Effect on Growth Factors and
Cytokines
Several growth factors and cytokines are involved in
the development of UFs, including transforming growth
factor-β (TGF-β), basic fibroblast growth factor (bFGF),
epidermal growth factor (EGF), platelet-derived growth
factor (PDGF), and vascular endothelial growth factor
(VEGF). Many of these growth factors are over-
expressed in UFs and alter the biological events
including increasing smooth muscle proliferation
(TGFβ, bFGF), increasing DNA synthesis (EGF,
PDGF), stimulating the synthesis of extracellular matrix
(TGF-β), promoting mitogenesis (TGF-β, EGF, IGF,
prolactin), or triggering angiogenesis (bFGF, VEGF).
Other growth factors including insulin like growth factor
(IGF), heparin-binding, TGF-α, tumor necrosis factor
alpha (TNF-α), basic fibroblast growth factor (FGF),
and acidic FGF are implicated in the development and
Alcohol Consumption and Risk of Uterine Fibroids Current Molecular Medicine, 2020, Vol. 20, No. 00 5
proliferation of UFs [65-68]. Additionally, cytokines may
be responsible for symptoms associated with UFs,
such as pain, infertility, and obstetric pathologies [59,
69].
Growth factors are interconnected to steroid
hormones. Progesterone may act by inducing the
production of growth factors and/or their respective
receptors. A study found that UFs growth is integrally
regulated by a complex crosstalk between sex steroid
hormones and growth factors. The authors studied the
molecular mechanisms of sex steroidal regulation of
UFs growth and apoptosis by evaluating the effects of
sex steroids and GnRH agonist on the expression of
growth factors and apoptosis-related factors. The study
showed that 17beta-estradiol upregulated EGF
receptor expression while downregulated p53 protein
expression levels in UFs cells [60], whereas
progesterone augmented EGF and anti-apoptotic Bcl-2
protein while inhibited IGF-I and TNF-α. EGF and IGF-I
are well known to act as local factors that stimulate
UFs growth [59, 70].
Transforming growth factor β (TGF-β) is a
polypeptide that consists of three isoforms: TGF-β1,
TGF-β2 and TGF-β3. TGF-βs are considered to be key
growth factors in the pathophysiology of UFs. They 1)
play an important role in cellular migration within the
tumor, 2) stimulate tumor growth, 3) enhance tumor
metabolism and decrease proteolytic degradation of
extracellular matrix (ECM) in UFs [71, 72]. The
expression of TGF-βs and their receptors are elevated
in UFs compared to normal myometrium [73- 75]. In
addition, overexpression of TGF-β mediators may be
responsible for clinically symptomatic UFs [71]. TGF-β3
is likely the most important isoform that implicated in
the pathogenesis of UFs. In addition, TGF- β3 has the
most significant role in overproduction of ECM; it
stimulates the expression of type 1 collagen,
proteoglycans, laminin and fibronectin [74, 76- 79].
Exposure of ovariectomized rats to ethanol for 2 to 4
weeks has been shown to increase the levels of TGF-
β3 and estrogen-regulated growth factors such as
basic FGF [80]. Moreover, a recent study showed that
elevated serum level of TGF- β3 was a risk factor for
the occurrence of UFs (71). Ethanol dependence
patients showed increased expression of TGF-β1 [81].
Tumor necrosis factor (TNF)-α is a pro-inflammatory
cytokine that is involved in the pathogenesis of UFs.
TNF-α is produced by macrophages which can be
found in UFs in a significant number. [69, 82]. TNF-α is
a cell-signaling protein that involved in systemic
inflammation and is one of the cytokines responsible
for the acute phase reaction. Higher TNF-α serum
concentration was found in women with clinically
symptomatic UFs [83]. Polymorphisms in gene
encoding TNF-α have been associated with an
increased risk of UFs [84]. However, serum TNF-α
level is elevated in alcoholics independently of any TNF
gene polymorphisms. Nevertheless, light-to-moderate
drinking had no significant effect on the levels of serum
TNF- α level [85].
4.3. Alcohol and Prolactin
Prolactin is a polypeptide hormone produced and
secreted from the anterior pituitary. It affects various
biological functions including reproduction. Literature
showed that prolactin is produced in UFs tissue, and its
higher level is a risk factor for UFs growth [86]. In
addition, elevated serum prolactin level has been
implied in UFs characteristics as well. A study found
that serum prolactin levels are positively correlated to
the number of UFs in patients’ uterus [87].
Several inhibitory and stimulatory signals secreted
from the hypothalamus can regulate the secretion of
the prolactin. One of these is the dopamine, which is
the main inhibitory factor responsible for inhibition of
prolactin release; hyperprolactinemia stimulates the
hypothalamus to release dopamine that stops further
prolactin release from the pituitary in the blood. Several
studies have shown an association between alcohol
intake in women and high levels of prolactin [43, 88-
92]. Animal studies have also shown an alcohol-
induced hyperprolactinemia phenomenon, one study
showed hyperprolactinemia occurred after acute
ethanol administration in female rats as well as chronic
self-administration of alcohol in a female monkey [93,
94]. Similarly, a study has found increased serum
prolactin level with chronic alcohol administration in
women [89]. Interestingly, Alcohol-induced
hyperprolactinemia can affect women of different ages
including postmenopausal women [95]. Alcohol
influences both the release and actions of the prolactin
[80, 96, 97]. Another study showed that ethanol causes
hyperprolactinemia both by increasing prolactin release
from lactotrops and by increasing the number of
lactotrops in the anterior pituitary gland [98]. Further
molecular analyses of the inhibitory action of
hypothalamic dopamine on pituitary prolactin secretion,
mediated by the dopamine G-protein–coupled D2
receptors (D2R), have been done. D2Rs interact with
regulatory molecules known as adenylyl-cyclase–
inhibitory Gi/Go (a subtype of G-proteins) [89, 99].
Chronic alcohol intake increases the gene expression
of prolactin in whole rats as well as primary cultures of
anterior pituitary cells [100]. In conclusion, different
patterns of alcohol consumption can lead to increased
serum prolactin level, which is a known risk factor that
promotes the developing of UFs.
Importantly, animal and human studies have
demonstrated that ethanol involves crosstalk with
estradiol-regulated cell-cell communication that
stimulates estradiol-mediated proliferation of lactotropic
cells in primary cultures of mixed anterior pituitary cells.
However, in cultures of only lactotropic cells, the
stimulation did not occur [80, 89, 98]. Interestingly,
ovariectomized rats has demonstrated that alcohol can
increase the risk of UFs even in the absence of the
estrogen source [101]. In addition, chronic alcohol
intake involved the suppression of dopamine D2
receptors inhibition of G proteins and intracellular cyclic
adenosine monophosphate (cAMP), it also modulated
TGF-β isoforms, their receptors (TGFBR2) and
consequently the factors secondary to TGF-beta
6 Current Molecular Medicine, 2020, Vol. 20, No. 00 Takala et al.
actions, including production of beta-bFGF from
follicular-stellate cells. Of note, the downstream
signaling that governs b-FGF production and secretion
involves activation of the MAP kinase p44/42-
dependent pathway. Collectively, a coordinated
suppression of D2 receptor- and TGFBR2 receptor-
mediated signaling, as well as enhancement of bFGF
activity, might be critical for ethanol action on prolactin
production and cell proliferation in lactotropes [89].
Remarkably, ethanol intake affects prolactin
production not only in adults but also in the developing
fetus. Exposure of the fetus from day 7 to day 21 of
gestation to alcohol has been demonstrated to increase
pituitary weight, pituitary prolactin mRNA and protein
content as well as prolactin plasma levels in female
rats compared to control animals [102]. This was
confirmed using agents that can prevent DNA
methylation and/or histone deacetylase activity, which
resulted in normalized D2R mRNA expression, pituitary
weight, and plasma prolactin levels in fetal alcohol-
exposed rats [102]. Finally, ethanol can affect the
prolactin levels via changes in the production and
secretion of growth factors in the pituitary that help
control lactotropic cell proliferation. Specifically, ethanol
exposure of ovariectomized rats for 2 to 4 weeks was
found to decrease the levels of growth-inhibitory
molecules while increase the levels of growth-
stimulatory factors, such as TGFβ-3 and basic FGF in
the pituitary gland; similar results were found in isolated
cell cultures enriched for lactotrops and exposed to
ethanol for 24 hours (80). Other studies clearly have
demonstrated that chronic alcohol consumption is a
positive risk factor for hyperprolactinemia [88, 95, 103,
104].
4.4. Alcohol and Vitamin D
Vitamin D is a steroid fat-soluble compound that has
extensively been studied. Its predominant source is
endogenous cutaneous synthesis (cholecalciferol or
D3), whereas dietary sources contribute to<20% of the
circulating levels of vitamin D (D3 and D2). The
endogenous, as well as the dietary sources of Vitamin
D, are inactive forms (prohormone). The circulating
(prohormone) is metabolized by a set of enzymes
(cytochrome P450 enzymes). In the liver CYP27A1
(hepatic 25-hydroxylase) converts the prohormone to
25- hydroxyl vitamin D (25-(OH) D), then in the
kidneys, converted to 1, 25-di-hydroxyvitamin D (1, 25
(OH)) which is the active metabolic form of the
hormone [105, 106]. Vitamin D is a key regulator of
calcium hemostasis [107].
Vitamin D has beneficial effects against UFs growth
that lead to the inhibition of tumor cell division and a
significant reduction in tumor size. These mechanisms
include regulation of cell proliferation and
differentiation, inhibition of angiogenesis, stimulation of
apoptosis of UFs cells, reduction of the TGF-β pro-
fibroid effect, modulating the expression of matrix
metalloproteinases (MMPs) and expression of the
tissue inhibitor of metalloproteinase (TIMPs) [13, 106,
108].
Administration of therapeutic doses of vitamin D3
was shown to significantly reduce UF size in the Eker
rat model [109]. In a similar manner, sufficient vitamin
D has a protective effect on UFs development in
women [107]. Recently, expanding number of studies
demonstrated the role of vitamin D in UFs
development. Using in vitro model of human UFs cells,
vitamin D inhibited proliferation of human UFs cells via
Catechol-O-Methyltransferase [110]. Another study
including 1036 premenopausal blacks and whites
American women with UFs, demonstrated that
sufficient serum vitamin D was capable of decreasing
the risk of UFs [111]. Another study investigated
vitamin D status (25- (OH) vitamin D) in women with
and without UFs, the study showed that 25-
hydroxyvitamin D3 was significantly lower in women
with UFs as compared with normal controls [14]. A
cross-sectional observational study supported the
protective role of vitamin D in decreasing UFs risk and
showed that lower serum 25-(OH) vitamin D levels
were significantly associated with the occurrence of
UFs. Furthermore, a statistically significant inverse
correlation was also observed between serum 25-(OH)
vitamin D levels and total UFs volume in black women
[13]. Both myometrial and UFs tissue growth in vitro
was effectively inhibited by 1,25(OH)2D3 (Bioactive
vitamin) in premenopausal women [112]. In addition,
other in vitro studies showed that vitamin D inhibited
the proliferation of immortalized UFs cells [108, 113].
Vitamin D has been found to play an important role
in regulating key factors and pathways that contribute
to the UFs phenotype. For example, vitamin D
(1,25(OH)2D3) reduces the expression of steroid
receptors in human UFs cells in laboratory conditions
(114), and increased levels of vitamin D was found to
inhibit TGF-β3 (113). Hypovitaminosis D is reversely
correlated with serum levels of TGF-β3 [115]. Vitamin
D supplements via regulating serum vitamin D
concentration are capable of decreasing the volume of
UFs [116].
Several studies have reported that the levels of
vitamin D were decreased with alcohol consumption
[117, 118]. Nevertheless, data concerning vitamin D
levels in individuals with alcohol use disorders remains
controversial. A positive association between alcohol
consumption and vitamin D deficiency has been
reported [119]. No significant association between
alcohol intake and vitamin D levels was also shown
[120]. Analysis of this controversy was explored in a
recent review using more recent studies with larger
sample sizes and focused more on specific populations
with conclusion of a positive association [121]. In
general, the data concerning vitamin D levels in
patients with alcohol use remain controversial. Well-
standardized research would be necessary to clear any
inconclusive information and to make unambiguous
data for the public about the real impact of alcohol
consumption on vitamin D serum levels. Fig. (1)
summarizes the effect of hormones, growth factors and
cytokines on alcohol–induced increased risk of UFs.
Alcohol Consumption and Risk of Uterine Fibroids Current Molecular Medicine, 2020, Vol. 20, No. 00 7
5. DEFECT OF ALCOHOL METABOLISM AND
UTERINE FIBROIDS.
Alcohol is metabolized by several pathways and
processes [122- 126]. However, there are two main
pathways; oxidative pathway that takes place mainly in
the liver and non-oxidative pathway that occurs mainly
in extrahepatic tissues [17]. The liver is the main site of
ethanol metabolism. Several enzymes are involved in
alcohol metabolism with either a major or a minor role.
Acetaldehyde is the first product of alcohol metabolism.
It produced from the oxidation of ethanol via the
catalytic enzyme alcohol dehydrogenase (ADH) [122],
then further metabolized to acetate by aldehyde
dehydrogenase enzyme (ALDH) which metabolizes the
majority of acetaldehyde in the body to acetate.
Acetate is then metabolized to water and carbon
dioxide [124].
Genetics is another line of evidence that supports
the link between UFs formation and polymorphism of
enzymes responsible for alcohol metabolism. A number
of studies have demonstrated that the expression of
alcohol dehydrogenase genes is downregulated in
UFs as compared with the myometrium tissues [51,
127]. A study showed how ethanol and acetaldehyde
could differentially affect the growth of human UFs and
myometrial cells. The study showed that acetaldehyde
significantly inhibited the growth of UFs cells as
compared with normal myometrium with decreased
levels of ALDH1 level in UFs cells [12]. Another recent
study has explored the role of alcohol dehydrogenase-
1 (ADH1) gene in the pathogenesis of UFs and
reported the alterations of expression patterns of
the ADH1 gene in human UFs tissue. The study
demonstrated that the ADH1 gene was significantly
downregulated in the UFs group compared to the
control group. Downregulation of the ADH1 gene
expression influences the transformation of the ECM,
which has a significant role in the etiology of UFs. A
negative correlation between tumor number and
decreased expression of ADH1 was also shown [127].
CONCLUSION
Alcohol consumption could affect several pathways
that are implicated in UFs risk/pathogenesis (Fig. 1). It
would be conceivable to establish a well-defined
research to demonstrate the actual impact of alcohol
consumption on the status of women with UFs.
Additionally, more cohort studies in human are needed
to characterize the alcohol-related UFs risk and
outcome in different populations. Furthermore, new
studies are needed to determine the alteration of
biological pathways and epigenome that contribute to
the UFs in response to alcohol exposure.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
This work was supported in part by NIH grants: RO1
ES028615, RO1 HD094378, RO1 HD087417, RO1 HD
094380, and U54 MD007602.
CONFLICT OF INTEREST
None of the authors has a financial relationship with
a commercial entity that has an interest in the subject
of this manuscript.
Fig. (1). Alcohol exposure and risk of Uterine Fibroids. Alcohol consumption alters the levels of various hormones, growth
factors and cytokines leading to increased risk of UF pathogenesis.
IGF-1: insulin-like growth factor 1; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor α
8 Current Molecular Medicine, 2020, Vol. 20, No. 00 Takala et al.
ACKNOWLEDGEMENTS
Declared None.
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