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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 249billion(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.
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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 womens 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 1844 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 23
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]. Alcoholinduced
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 wellknown suppressor of
the hypothalamicpituitary unit [34]. Therefore, an
increase in testosterone could disturb normal female
cycling and decrease IGF–1 level in the bloodstream.
IGF1 evokes LHRH (Luteinizing hormone-releasing
hormone) release in female rats [35, 36]. Moreover, in
acute alcohol studies, the ability of IGF1 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!
Age
(yrs.)!
Outcome !
Public-
ation
Year!
Authors!
Refe-
rences!
Current
alcohol
intake !
Prospectiv
e cohort!
USA!
September 1989 -
May 1993
(Nurses' Health
Study II)!
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!
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)!
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!
!
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)!
2584!
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!
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!
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-proteincoupled 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 alcoholinduced 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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... Other important risk factors include obesity [4-6]. Individual and environmental risk factors associated with tobacco smoking and alcohol abuse can also contribute to the formation of uterine fibroids [7,8]. ...
... It has been stated that inflammatory conditions in both general and local endometrium can be effective in causing uterine fibroids with different mechanisms such as increased ECM protein, expression of cytokines, etc. [8][9][10]. If the uterus had chronic inflammation by inflammatory factors such as injury, infection, menstruation inflammations, etc., it causes the imbalance of the immune system through increased T helper cytokines and decreased function of target cells (Tregs) and the inflammatory response of the immune system leads to fibrosis tissue formation and proliferation. ...
... In addition, various growth factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF) [12], exert effects on the myometrium and leiomyoma, contributing to the pathophysiology of uterine leiomyomatosis. Risk factors for uterine leiomyomatosis include older age, race, nulliparity, premenopause, family history of uterine leiomyomatosis, hypertension (HTN), food additives, soy milk, obesity, low vitamin D levels, high vitamin E levels, microbiome change, endocrinedisrupting chemicals, smoking, and alcohol consumption [2,[13][14][15][16][17][18][19][20][21][22][23][24][25]. ...
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Background Uterine leiomyomatosis and psoriasis are prevalent conditions and shared pathophysiological factors indicate a potential association. However, a direct correlation has not been established. We investigated the relationship between uterine leiomyomatosis and the risk of new-onset psoriasis in Korean females of reproductive age. Methods This nationwide population-based study used data from the Korean National Health Insurance System database. Data from 2,755,790 Korean females 20–39 years of age who underwent health check-ups from 2009 to 2012 were analyzed. Monitoring began at the initial national health assessment within the time frame and continued until either the diagnosis of emerging psoriasis or until December 2018. Results Among 2,503,769 females included, 1.96% were diagnosed with psoriasis and 0.72% with uterine leiomyomatosis. The incidence ratio for new-onset psoriasis was higher in uterine leiomyomatosis patients (3.13 per 1,000) than in subjects without uterine leiomyomatosis (2.72 per 1,000). The hazard ratio for psoriasis occurrence was 1.18 (1.07–1.31) in uterine leiomyomatosis patients, 1.22 (1.08–1.37) in subjects who did not undergo myomectomy, and 1.12 (0.94–1.33) in patients who underwent myomectomy. Conclusions Uterine leiomyomatosis patients, especially those not undergoing myomectomy, showed an increased risk of psoriasis. Lifestyle modifications and surgical intervention for uterine leiomyomatosis may also be beneficial for psoriasis occurrence.
... В таких случаях чаще встречаются узлы больших размеров, существовавшие много лет, поэтому установление и учет диагнозов запаздывают [16]. Другой особенностью является зависимость опухоли от возраста, расы, образа жизни и региона проживания на планете [17,18]. Некоторые исследователи показали, что существует положительная зависимость между риском заболеваемости ЛМ и афроамериканской этнической принадлежностью [19]. ...
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Background. Uterine fibroid (UF) is a benign tumor of the myometrium and is considered as one of the criteria for the state of women’s reproductive health. Objective information about the incidence of UF in a modern megalopolis allows us to assess the level of health of the female population, characterize the availability and quality of medical care, and plan its development. Aim. To analyze the incidence and prevalence of UF according to the data of medical organizations in Yekaterinburg in 2016–2022. Materials and methods. An epidemiological study of the incidence and prevalence of the adult female population of the city of Yekaterinburg in 2016–2022 was conducted. For the analysis, we used Form No. 12 of the Federal Statistical Observation of Medical Organizations located in the city. The incidence rates were calculated for the average annual female population aged 18 years and over, expressed in ⁰ / 0000 . Absolute growth (decrease), growth rate (decrease), growth rate (decrease), average growth rate (decrease) were studied. The long-term dynamics of the indicators was determined using the average growth rate. Results. The incidence of UF was 130.89 ⁰ / 0000 , and the prevalence was 735.80 ⁰ / 0000 in 2016. During the pre-pandemic period, the indicators increased significantly in 2019 compared to the baseline year 2016 ( р < 0.001). The incidence increased by 1.96 times, the prevalence – by 1.39 times. The indicators decreased to the level of 2016 during the pandemic of new coronavirus infection (2020–2022) ( р >0.05). Conclusion. The obtained dynamics of incidence and prevalence of UF in the population of women in a modern megalopolis is considered as a criterion for the state of women’s health, accessibility and quality of preventive and planned medical care for gynecological patients. The results of the study are recommended for planning medical care for women and can form the basis for continuing epidemiological studies.
... Drinking might affect blood lipids differently during different age stages. Third, drinking alcohol is associated with high levels of steroid hormones, which may increase the effect of steroid hormones on lowering total cholesterol [33]. In the two above-mentioned studies [14,15] on the association between alcohol consumption and blood lipids, the conclusions were also inconsistent, with one suggesting that there is a significant positive association between alcohol consumption and blood lipids [15], and the other that there was no such association [14]. ...
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Background Alcohol consumption by children and adolescents is receiving increasing attention. It may cause dyslipidemia, a risk factor for cardiovascular disease. However, the association between alcohol consumption and blood lipids in children and adolescents is unclear, and so we aimed to characterize this association. Methods Data from the China Health and Nutrition Survey were extracted from children and adolescents aged 7–18 years for whom information was available on alcohol consumption. The population was divided into drinking and nondrinking groups. The χ2, Student’s t, or Mann–Whitney U test was used to compare groups. Univariate and multivariate linear regression and propensity score matching (PSM) analysis were used to identify the association between alcohol consumption and blood lipids. Results This study included 408 children and adolescents with 35 drinkers and 373 nondrinkers. The drinkers had significantly lower values of total cholesterol (TC) (3.8 mmol/L for nondrinkers versus 3.5 mmol/L for drinkers, p = 0.002) and high-density lipoprotein cholesterol (HDL-C) (1.3 mmol/L for nondrinkers versus 1.2 mmol/L for drinkers, p = 0.007), but not for low-density lipoprotein cholesterol (LDL-C) (2.1 mmol/L for nondrinkers versus 2.0 mmol/L for drinkers, p = 0.092) or triglyceride (TG) (0.9 mmol/L for nondrinkers versus 0.8 mmol/L for drinkers, p = 0.21). The univariate and multivariate analyses led to the same conclusions. After PSM there was still a significant negative association between alcohol consumption and TC or HDL-C. Conclusion Alcohol consumption in children and adolescents exhibited significant negative associated with TC and HDL-C, but not with LDL-C or TG. These findings need to be confirmed in future prospective research, and the health effects of blood lipid changes caused by drinking in children and adolescents need to be clarified.
... Fibroids have been shown to produce prolactin and have higher local levels of oestradiol, which may have an impact on fertility. Furthermore, there is a connection between the pathophysiology of uterine broids and alcohol 7 consumption. Overall, the development of broids in India is attributed to a mix of modiable and non-modiable risk factors. ...
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Complex in nature and classied according to where they occur in the uterine layers, uterine broids are impacted by a wide range of risk factors, such as age, race, parity, and lifestyle decisions that have an impact on a woman's life. A cross-sectional study conducted in a private medical college found a signicant prevalence of uterine broids among women aged 20 or older. The study found a prevalence of 66.6%, with intramural broids dominating at 80.5%. Menorrhagia was the most common symptom, with the majority falling into the 40-49 age range. Signicant associations were found between broid diagnosis, menopausal status, age, oral contraceptive pill use, and hypertension. The study also highlighted the need for customised healthcare interventions in rural Palghar district to address the complex issues raised by uterine broids.
... Отдельную роль H. Takala и соавт. отводят алкоголю, оказывающему отрицательное влияние на репродуктивную функцию женщины и инициацию ЛММ [16]. ...
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Aim. To identify risk factors for uterine leiomyoma (ULM) in women of reproductive age based on the study of clinical and medical history features in various tumor types. Materials and methods. The study included 82 women of reproductive age with symptomatic ULM (the main group) and 47 somatically healthy women of reproductive age without proliferative gynecological diseases who underwent elective treatment at the Gorodkov Ivanovo Research Institute of Motherhood and Childhood (Director is professor AI Malyshkina, MD, Ph.D.). The study patients underwent general clinical examinations, ultrasound examination of the pelvic organs, histological examination of endometrial biopsy specimens, and myomatous nodes in women of the main group. Results. The following risk factors and clinical and history features were identified in women with uterine fibroids: late reproductive age (p=0.000), unregistered marriage (p=0.026), employment (p=0.006), history of profuse and painful menstruation (p=0.000 and p=0.000, respectively), inflammatory diseases of the respiratory system (p=0.003), pain syndrome and profuse menstruation (p=0.000 and p=0.000, respectively), endometrial hyperplasia without atypia, and chronic endometritis according to histological examination (p=0.000 and p=0.000, respectively). When comparing the subgroups "Ki67+" and "Ki67-", we obtained the following clinical and history features in women with proliferating uterine fibroids: varicose disease of the lower extremities (p=0.035); and when comparing the subgroups "with secondary changes" and "without secondary changes", we found a higher rate of pain (p=0.038) in women with secondary changes in the myomatous node, as well as a tendency to a higher rate of painful menstruation (p=0.093) and endometrial hyperplasia (p=0.093). Conclusion. Risk factors for ULM in women of reproductive age can be divided into modifiable ones, which include social disadvantage (unregistered marriage, hard physical work), inflammatory factor (inflammatory diseases of the respiratory system) and unmodifiable (late reproductive age). Clinical and history features of women with Ki67+ ULM compared to women with Ki67- ULM include more frequent use of barrier contraception, high prevalence of varicose vein disease of the lower extremities, and surgical interventions on the pelvic organs. Also, according to histological examination, women with ULM with secondary changes in the myomatous node, compared to women with ULM without secondary changes in the myomatous node, have a higher prevalence of painful menstruation, pain syndrome, and concomitant endometrial hyperplasia.
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Background Uterine fibroids (UFs), the most common tumors in women worldwide, may reduce quality of life and daily activities and even lead to adverse fertility and general health events in patients, causing significant societal health and financial burdens. The objective was to evaluate the global burden through epidemiological trends and examine the potential risk factors for UFs at the national level. Methods Data on the incidence, prevalence, disability-adjusted life years (DALYs), age-standardized incidence rates (ASIRs), age-standardized prevalence rates (ASPRs), and age-standardized DALY rates for UFs were collected, and the associations with the Human Development Index (HDI) and fertility were evaluated. The age trends in the average annual percent change (AAPC) of the incidence and prevalence rates of UFs were evaluated by joinpoint regression analysis. The associations between lifestyle, metabolic, and socioeconomic factors and the ASIRs of UFs were examined using multivariable linear regression analysis. Results The worldwide incidence and prevalence of UFs have been increasing in the past decade, with AAPCs of 0.27% in the incidence rate and 0.078% in the prevalence rate. During 2010–2019, significant increasing trends in UF ASIR were observed in 52 of 88 countries. The age-specific incidence and prevalence of UFs in most age groups showed increasing trends except for 45–54-year-old women which showed no significant trend. Ecological analysis demonstrated no relationship between the incidence of UFs and the HDI but an inverse association with fertility. The incidence of UFs was positively correlated with alcohol intake, hypertension, overweight, and obesity and negatively correlated with smoking. Conclusion With the increasing incidence and prevalence worldwide, effective targeted prevention and control of relevant risk factors at the national level should be encouraged to reduce the disease burden of UFs.
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The present work was carried out to evaluate the possible effects of chronic alcohol intake on the histology and ultrastructure of the endometrial lining epithelium of the uterine horn of Calomys callosus. 20 adult female rodents, Calomys callosus, three months old, were used. These animals were divided equally into 2 experimental groups called control and alcoholic. The control group received a solid diet (mouse food) and tap water “ad libitum”. The alcoholic group received the same solid diet and ethanol was diluted to 20% in water. At the end of 120 days of treatment with 20% alcohol, all animals were anesthetized with ethyl ether and sacrificed. Daily observations of the animals’ behavior, carried out throughout the treatment period, made it possible to verify a certain lethargy of the animals in the alcoholic group, concerning the animals in the control group, regarding responses to physical and sound stimuli. Macroscopically, no difference was observed in the uterus between the groups analyzed. In light microscopy, the animals in the alcoholic group showed the same histological characteristics as the control group, however, a marked atrophy of the epithelial tissue covering the endometrium could be observed. This atrophy is confirmed by the results of transmission electron microscopy, where important changes were also observed in alcoholic animals: a large increase in lipid droplets, dispersed throughout the cytoplasm, digestive vacuoles, and an increase in the cisterns of the granular endoplasmic reticulum. The presence of invasive immune cells in the epithelial tissue was also observed. Scanning electron microscopy analyses showed the presence of lipid droplets in the endometrial lumen. Ethanol ingestion caused epithelial lesions in the uterine horn, causing apoptosis, and interfering with the secretory mechanism.
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Uterine fibroids (UFs) are common tumors in women of reproductive age. It is imperative to comprehend UFs’ associated risk factors to facilitate early detection and prevention. Simple relying on surgical/pharmacological treatment of advanced disease is not only highly expensive, but it also deprives patients of good quality of life (QOL). Unfortunately, even if the disease is discovered early, no medical intervention is traditionally initiated until the disease burden becomes high, and only then is surgical intervention performed. Furthermore, after myomectomy, the recurrence rate of UFs is extremely high with the need for additional surgeries and other interventions. This confused approach is invasive and extremely costly with an overall negative impact on women’s health. Secondary prevention is the management of early disease to slow down its progression or even halt it completely. The current approach of watchful observation for early disease is considered a major missed opportunity in the literature. The aim of this article is to present an approach named the ESCAPE (Evidence-Based Approach for Secondary Prevention) of UF management. It comprises simple, inexpensive, and safe steps that can arrest the development of UFs, promote overall reproductive health, decrease the number of unnecessary surgeries, and save billions of health care systems’ dollars worldwide.
Article
Uterine fibroids grow in the myometrium and are benign tumors. The etiology and molecular mechanism are not fully understood. Here, we hope to study the potential pathogenesis of uterine fibroids by bioinformatics. Our aim is to search for the key genes, signaling pathways and immune infiltration about the development of uterine fibroids. The GSE593 expression profile was downloaded from the Gene Expression Omnibus database, which contains 10 samples, including 5 uterine fibroids samples and 5 normal controls. Bioinformatics methods were used to find differentially expressed genes (DEGs) in tissues and further analyze the DEGs. R (version 4.2.1) software was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analysis of DEGs in uterine leiomyoma tissues and normal control. STRING database was used to generate protein-protein interaction (PPI) networks of key genes. Then, CIBERSORT was used to assess the infiltration of immune cells in uterine fibroids. A total of 834 DEGs were identified, of which 465 were up-regulated and 369 were down-regulated. GO andKEGG pathway analysis showed that the DEGs were mainly concentrated in extracellular matrix and cytokine related signaling pathways. We identified 30 key genes in DEGs from the PPI network. There were some differences in infiltration immunity between the 2 tissues. This study indicated that screening key genes, signaling pathways and immune infiltration by comprehensive bioinformatics analysis is helpful to understand the molecular mechanism of uterine fibroids and provide new insights into understanding the molecular mechanism.
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Context: Although uterine fibroids (UFs) continue to place a major burden on female reproductive health, the mechanisms behind their origin remain undetermined. Normal myometrial stem cells may be transformed into tumor-initiating stem cells, causing UFs, due to unknown causes of somatic mutations in MED12, found in up to 85% of sporadically formed UFs. It is well established in other tumor types that defective DNA repair increases the risk of such tumorigenic somatic mutations, mechanisms not yet studied in UFs. Objective: To examine the putative cause(s) of this stem cell transformation, we analyzed DNA repair within stem cells from human UFs compared to those from adjacent myometrium to determine whether DNA repair in fibroid stem cells is compromised. Design: Human fibroid (F) and adjacent myometrial (Myo) stem cells were isolated from fresh tissues, and gene expression relating to DNA repair was analyzed. Fibroid stem cells differentially expressed DNA repair genes related to DNA double- (DSBs) and single-strand breaks. DNA damage was measured using alkaline comet assay. Additionally, DNA DSBs were induced in these stem cells and DNA DSB repair evaluated (1) by determining changes in phosphorylation of DNA DSB-related proteins and (2) by determining differences in γ-H2AX foci formation and relative DNA repair protein RAD50 expression. Results: Overall, F stem cells demonstrated increased DNA damage and altered DNA repair gene expression and signaling, suggesting that human F stem cells demonstrate impaired DNA repair. Conclusions: Compromised F stem cell DNA repair may contribute to further mutagenesis and, consequently, further growth and propagation of UF tumors.
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Uterine fibroids (UFs) are one of the most common pathologies of the female genital tract. The incidence of UFs has been estimated at 25–80%. Tumor necrosis factor (TNF)-α is a cell-signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. The aim of the study was to evaluate the impact of clinically symptomatic UFs on TNF-α serum levels. A total of 149 Caucasian women were included: 85 patients admitted for surgery due to clinically symptomatic UFs (n = 85; study group) and 64 age-matched UF-free controls (n = 64). TNF-α serum concentrations between the groups were compared. Receiver operating characteristic (ROC) curves were also used as a statistical model to evaluate TNF-α as a marker for UFs. Mean TNF-α serum concentration in the study group was 0.34 ± 0.14 pg/mL; (in half of the subjects, the level did not exceed 0.39 pg/mL. Mean TNF-α serum concentration in the control group was 0.17 ± 0.09 pg/mL; in half of the subjects, the level did not exceed 0.14 pg/mL. The difference was statistically significant. Using the area under the ROC curve, we found that TNF-α serum concentration of 0.34 pg/mL can be used as a predictor for UFs in selected populations. In our study, we confirmed higher TNF-α serum concentrations in women with clinically symptomatic UFs.
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Despite the major negative impact uterine fibroids (UFs) have on female reproductive health, little is known about early events that initiate development of these tumors. Somatic fibroid-causing mutations in MED12, the most frequent genetic alterations in UFs (up to 85% of tumors), are implicated in transforming normal myometrial stem cells (MSCs) into tumor-forming cells, though the underlying mechanism(s) leading to these mutations remains unknown. It is well-accepted that defective DNA repair increases the risk of acquiring tumor-driving mutations, though defects in DNA repair have not been explored in UF tumorigenesis. In the Eker rat UF model, a germline mutation in the Tsc2 tumor suppressor gene predisposes to UFs, which arise due to “second hits” in the normal allele of this gene. Risk for developing these tumors is significantly increased by early-life exposure to endocrine-disrupting chemicals (EDCs), suggesting increased UF penetrance is modulated by early drivers for these tumors. We analyzed DNA repair capacity using analyses of related gene and protein expression and DNA repair function in MSCs from adult rats exposed during uterine development to the model EDC diethylstilbestrol (DES). Adult MSCs isolated from developmentally-exposed rats demonstrated decreased DNA end-joining ability, higher levels of DNA damage, and impaired ability to repair DNA double-strand breaks (DSBs) relative to MSCs from age-matched, vehicle-exposed rats. These data suggest that early-life developmental EDC-exposure alters these MSCs’ ability to repair and reverse DNA damage, providing a driver for acquisition of mutations that may promote the development of these tumors in adult life.
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Background The published data about alcohol consumption and uterine myoma are scanty and controversial: some studies found positive association whereas other studies showed no association. Objectives To conduct a systematic review and meta-analysis to determine whether alcohol is a risk factor for myoma. Search strategy A MEDLINE/EMBASE search was carried out, supplemented by manual searches of bibliographies of the selected studies. Selection criteria Articles published as full-length papers in English. In the review we included all identified studies. Otherwise, the inclusion criteria for studies included in the meta-analysis were: a) case-control or cohort studies, reporting original data; b) studies reporting original data on the association between alcohol consumption and myoma; c) diagnosis of myoma was ultrasound or histological confirmed and/or clinically based. Data collection and analysis A total of 6 studies were identified for the review and 5 studies were included in the meta-analysis. The primary outcome was the incidence of uterine myoma in ever versus never alcohol drinkers and when data were available, we also analyzed categories of alcohol intake. We assessed the outcomes in the overall population and then we performed a subgroup analysis according to study design. Pooled estimates of the odds ratios (OR) with 95% confidence interval (CI) were calculated using random effects models. Main results The summary OR (95%CI) of myoma forever versus never alcohol intake was 1.12 (0.94–1.34) with significant heterogeneity. The summary OR for current versus never drinking was 1.33 (1.01–1.76) with no heterogeneity. Conclusions Ever alcohol consumption is not associated with myoma risk. Based on the data of two studies, current alcohol drinkers had a slightly borderline increased risk of diagnosis of myoma. In consideration of the very limited number of studies and the suggestion of a potential increased risk among current drinkers, further studies are required.
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Uterine fibroids (UFs) are benign tumors of the female genital tract made of the smooth muscle of the uterus. UF growth depends mostly on the influence of the steroid hormones and selected growth factors. Transforming growth factor β (TGF-βs) is a polypeptide that consists of three isoforms: TGF-β1, TGF-β2, and TGF-β3. At present, TGF-β is considered to be one of the key factors in the pathophysiology of UFs. It plays a major role in cellular migration within the tumor, stimulates tumor growth, and enhances tumor metabolism. As a consequence of various dependencies, the synthesis and release of TGF-β in a UF tumor is increased, which results in excessive extracellular matrix production and storage. High concentrations or overexpression of TGF-β mediators may be responsible for clinically symptomatic UFs. The aim of this review was to check the available evidence for the influence of the TGF-β family on UF biology. We conducted their search in PubMed of the National Library of Medicine with the use of the following selected keywords: “uterine fibroid”, “leiomyoma”, and “transforming growth factor β”. After reviewing the titles and abstracts, more than 115 full articles were evaluated. We focused on the TGF-β-related molecular aspects and their influence on the most common symptoms that are associated with UFs. Also, we described how the available data might implicate the current medical management of UFs.
Article
Fetal alcohol exposure results in well-characterised neuro-behavioural deficits in offspring, which form the basis for diagnosing fetal alcohol spectrum disorder. However, there is increasing interest in the full range of health complications that can arise in children and adults with this disorder. We used a systematic review approach to locate all clinical and preclinical studies across a broad range of health outcomes in offspring exposed to prenatal alcohol. Our search encompassed four databases (PubMed, CINAHL, Embase and Web of Science) and titles/abstracts from retrieved studies were screened against strict inclusion/exclusion criteria. This review specifically evaluated studies reporting on reproductive outcomes in both males and females. A total of 23 studies were included, 5 clinical and 18 preclinical. Although there was a wide range in the quality of reporting across both clinical and preclinical studies, and variable results, trends emerged amongst the reproductive measures that were investigated. In females, most studies focussed on age at first menarche/puberty onset, with evidence for a significant delay in alcohol-exposed offspring. In males, offspring exposed to prenatal alcohol had altered testosterone levels, reduced testes and accessory gland weights and reduced sperm concentration and semen volume. However, further studies are required due to the paucity of clinical studies, the narrow scope of female reproductive outcomes examined and inconsistencies in outcomes across preclinical studies. We recommend that adolescents and individuals of reproductive age diagnosed with fetal alcohol spectrum disorder be assessed for reproductive dysfunction to allow appropriate management of their reproductive health and fertility.
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Uterine fibroids (UFs) are the most frequent gynecologic tumors, affecting 70 to 80% of women over their lifetime, Although these tumors are benign, they can cause significant morbidity and may require invasive treatments such as myomectomy and hysterectomy in premenopausal women at a cost of up to $34 billion per year. Many risk factors for these tumors have been identified, including environmental exposures to endocrine-disrupting chemicals such as genistein and diethylstilbestrol (and other environmental agents) resulting in hyper-responsiveness to hormone in the adult uterus and promotion of hormone-dependent UFs. Although the molecular mechanisms underlying the pathogenesis of UFs is largely unknown, a growing body of evidence implicates unfavorable early-life environmental exposure and multiple biological pathways express as potentially import contributors. In this article, we will review the role of genetic and epigenetics in the conversion of myometrial stem cells to tumor (fibroid) initiating cells, and their role in UF development.
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Risk factors, both modifiable and non-modifiable, are associated with the development of fibroids. These include age, race, endogenous and exogenous hormonal factors, obesity, uterine infection, and lifestyle (diet, caffeine and alcohol consumption, physical activity, stress, and smoking). Some of the epidemiological data were conflicting; consequently, further studies are needed to better understand the factors that influence fibroid prevalence.
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Research carried out during the past two-decades extended the understanding of actions of vitamin D, from regulating calcium and phosphate absorption and bone metabolism to many pleiotropic actions in organs and tissues in the body. Most observational and ecological studies report association of higher serum 25-hydroxyvitamin D [25(OH)D] concentrations with improved outcomes for several chronic, communicable and non-communicable diseases. Consequently, numerous agencies and scientific organizations have developed recommendations for vitamin D supplementation and guidance on optimal serum 25(OH)D concentrations. The bone-centric guidelines recommend a target 25(OH)D concentration of 20 ng/mL (50 nmol/L), and age-dependent daily vitamin D doses of 400-800 IU. The guidelines focused on pleiotropic effects of vitamin D recommend a target 25(OH)D concentration of 30 ng/mL (75 nmol/L), and age-, body weight-, disease-status, and ethnicity dependent vitamin D doses ranging between 400-2,000 IU/day. The wise and balanced choice of the recommendations to follow depends on one's individual health outcome concerns, age, body weight, latitude of residence, dietary and cultural habits, making the regional or nationwide guidelines more applicable in clinical practice. While natural sources of vitamin D can raise 25(OH)D concentrations, relative to dietary preferences and latitude of residence, in the context of general population, these sources are regarded ineffective to maintain the year-round 25(OH)D concentrations in the range of 30–50 ng/mL (75-125 nmol/L). Vitamin D self-administration related adverse effects, such as hypercalcemia and hypercalciuria are rare, and usually result from taking extremely high doses of vitamin D for a prolonged time.