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Gynecological Endocrinology
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Alpha lipoic acid in obstetrics and gynecology
Chiara Di Tucci, Mara Di Feliciantonio, Flaminia Vena, Carmela Capone,
Michele Carlo Schiavi, Daniela Pietrangeli, Ludovico Muzii & Pierluigi
Benedetti Panici
To cite this article: Chiara Di Tucci, Mara Di Feliciantonio, Flaminia Vena, Carmela Capone,
Michele Carlo Schiavi, Daniela Pietrangeli, Ludovico Muzii & Pierluigi Benedetti Panici
(2018): Alpha lipoic acid in obstetrics and gynecology, Gynecological Endocrinology, DOI:
10.1080/09513590.2018.1462320
To link to this article: https://doi.org/10.1080/09513590.2018.1462320
Published online: 04 May 2018.
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REVIEW ARTICLE
Alpha lipoic acid in obstetrics and gynecology
Chiara Di Tucci , Mara Di Feliciantonio, Flaminia Vena, Carmela Capone, Michele Carlo Schiavi,
Daniela Pietrangeli, Ludovico Muzii and Pierluigi Benedetti Panici
Department of Gynecological, Obstetrical and Urological Sciences, ‘‘Sapienza’’ University of Rome, Rome, Italy
ABSTRACT
Alpha-Lipoic acid (ALA) is a natural antioxidant synthetized by plants and animals, identified as a catalytic
agent for oxidative decarboxylation of pyruvate and a-ketoglutarate. In this review, we analyzed the
action of ALA in gynecology and obstetrics focusing in particular on neuropathic pain and antioxidant
and anti-inflammatory action. A comprehensive literature search was performed in PubMed and Cochrane
Library for retrieving articles in English language on the antioxidant and anti-inflammatory effects of ALA
in gynecological and obstetrical conditions. ALA reduces oxidative stress and insulin resistance in women
with polycystic ovary syndrome (PCOS). The association of N-acetyl cysteine (NAC), alpha-lipoic acid (ALA),
and bromelain (Br) is used for prevention and treatment of endometriosis. In association with omega-3
polyunsaturated fatty acids (n-3 PUFAs) with amitriptyline is used for treatment of vestibulodynia/painful
bladder syndrome (VBD/PBS). A promising area of research is ALA supplementation in patients with
threatened miscarriage to improve the subchorionic hematoma resorption. Furthermore, ALA could be
used in prevention of diabetic embryopathy and premature rupture of fetal membranes induced by infla-
mation. In conclusion, ALA can be safely used for treatment of neuropatic pain and as a dietary support
during pregnancy.
ARTICLE HISTORY
Received 17 January 2018
Revised 18 March 2018
Accepted 4 April 2018
Published online 3 May 2018
KEYWORDS
Alpha-lipoic acid;
antioxidant; neuropatic
pain; threatened
miscarriage; polycystic
ovary syndrome
Introduction
Alpha-lipoic acid (ALA) is a natural antioxidant lipophilic com-
pound which acts as an essential cofactor for mitochondrial
enzymes. It increases the effectiveness of other antioxidants as
glutathione by 30–70%, especially in liver, lung and kidney cell
cultures in a laboratory [1,2]. The complex ALA-DHLA inter-
venes in the repair of proteins lipids and DNA damaged by oxi-
dation [3]. ALA has been used in patients with type-2 diabetes to
improve glycemic control and to reduce symptoms of diabetic
neuropathy and has gained attention in the last years for the
treatment of liver and neurological diseases.
In this review, we analyzed the action of ALA in gynecology
and obstetrics focusing on its antioxidant and anti-inflamma-
tory action.
Alpha-lipoic acid in polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) affects 4%to 12%of repro-
ductive age women and is characterized by hyperandrogenemia,
amenorrhea and anovulation [4].
Recent evidence shows that oxidative stress is increased in
PCOS women because of an increased production of free radicals
followed by decreased serum antioxidant levels and antioxidant
enzyme activity. The increased oxidant status appears to worsen
the insulin resistance state [5].
ALA plays a role in the regulation of glucose and lipid metab-
olism by stimulating glucose uptake with an intracellular redistri-
bution of GLUT1 and GLUT4 glucose transporters, similar to
that caused by insulin [6].
Growing evidence suggests that alpha lipoic acid may improve
reproductive function and metabolic parameters in women
affected by PCOS.
One recent study assessed the efficacy of a combination of
400 mg of alpha lipoic acid and 1 g of myo-inositol in reducing
insulin resistance and glucose-load induced hyperinsulinemia in
a group of 36 PCOS patients, improving also gonadotropin secre-
tion. All the patients had a significant reduction of LH serum
levels and LH/FSH ratio, however only hyperinsulinemic PCOS
patients did show variations in Homeostasis Model Assessment
Insulin Resistance index (HOMA-IR) and response to oral glu-
cose tolerance test (OGTT) that indicated a significant increase
in isulin sensitivity [7].
Alpha lipoic acid plus myo-inositol, in addition to treatment
with metformin 1.7 g, also showed a better response in terms of
hyperandrogenism, BMI and HOMA index than metformin 3 g
alone in women with PCOS [8].
Rago et al. evaluated the effects of a cycle of treatment 2 g of
myo-inositol and 800 mg of ALA per die in a group of 37 nonob-
ese PCOS patients who had undergone ICSI and did not obtain a
pregnancy. After 3 months of treatment, significant effects in
insulin levels, BMI and ovarian volume were obsereved, although
the pregnancy rate and the oocytes quality were similar to
patients who assumed myo-inositol alone [9].
In another recent study, 30 young women affected by PCOS
with insulin resistance were treated either with an association of
1 g myo-inositol, 5 mg monacolin K and 400 mg lipoic acid for 6
months or a double dosage of 2 g myo-inositol, 10 mg monacolin
K, 800 mg lipoic acid for 6 months. When combined with mona-
colin K, a natural statin, the treatment with myo-inositol and
CONTACT Chiara Di Tucci chiara.ditucci@uniroma1.it Department of Gynecology and Obstetrics Science and Urologic Sciences, University of Rome “Sapienza”,
V. le del Policlinico 155, 00161 Rome, Italy
ß2018 Informa UK Limited, trading as Taylor & Francis Group
GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2018.1462320
ALA showed a dose-dependent improvement in BMI, dyslipide-
mia and hyperandrogenism-associated symptoms like hirsutism
and menstrual disorders [10]. Treatment with a combination of
1 g D-chiro-inositol (DCI) and 600 mg ALA daily for 180 days
versus no treatment in a group of forty-six women (26 study
group subjects and 20 controls) of reproductive age with PCOS
led to similar results in terms of clinical and metabolic features.
In fact, in the study group HOMA-IR, insulin levels, lipid profile
and frequency of menstrual cycles were significantly improved
[5]. Masharani et al. administrated a preparation of controlled-
release ALA 600 mg twice a day for 16 weeks in a group of 6 lean
women affected by PCOS. Despite the absence of severe insulin
resistance in this group of patients, a therapy with controlled-
release ALA led to a lowering of triglyceride levels, improvement
in insulin sensitivity and menstrual frequency [4]. Genazzani
et al in a recent study describe the improving in metabolic
impairment in obese PCOS women especially with a history of
familiar diabetes with daily 400 mg of ALA oral assumption.
Practically ALA administration improved insulin sensitivity, espe-
cially in those patients with diabetic relatives with a defect in
function and/or mitochondrial LASY (lipoic acid synthase) syn-
thesis. It is interesting to note that a decrease of triglyceride and
GOT plasma levels greatly improved and/or protected liver func-
tion in these patients, reducing the risk to develop a liver impair-
ment [11].
Use of alpha-lipoic acid to improve outcome in
infertility
In vitro follicular development and maturation are affected by
many factors and oxidative stress (OS) seems to have a pivotal
role [12].
Under physiological conditions, generation of reactive oxygen
species (ROS) occurs during various cellular metabolic reactions,
which are equilibrated by antioxidant defense systems. In the in
vitro setup, higher oxygen levels and lack of physiological defense
mechanisms against ROS result in OS [13]. Also, it has been
shown that, OS can be induced during assisted reproductive tech-
nique procedure by manipulation of gametes and embryos [14].
Talebi et al investigated the effect of ALA on culture mouse
isolating preantral follicles. ALA (100uM) increased follicular
total antioxidant capacity (TAC) levels, decreased ROS levels,
and finally improved the developmental competence of preantral
follicles in vitro. In the presence of 100 uM ALA, developmental
rates of follicles, oocytes and embryos were significantly higher
than other groups (p<.05) [15]. Zavereh et al confirmed that
ALA decreased ROS and increased TAC but could not affect
maturation rate of both cumulus oocyte complexes (COCs) and
denuded oocytes (DOs) in one or two step in vitro maturation
manner [16].
In one study performed by Avci et al. [17], the effect of ALA
and alfa-tocopherol (ATF), in preventing the toxic effect induced
by the exposure to Bisphenol A (BPA) –a commonly used
material in daily life which it is argued to cause oxidative stress
in and ovarian tissue –was studied.
Apart from their endocrine disrupting effect, studies have
shown that they cause cellular damage to protein and lipid struc-
tures through ROS in the tissues where BPA accumulates [18].
The administration of ALA (100 mg/kg/day) and ATF (20 mg/kg/
day) to female rats for 30 days prevented lipid peroxidation in
the liver and ovaries of female rats caused by the administration
of BPA.
Furthermore, aging and age-related pathologies are frequently
associated with loss of mitochondrial function mainly due to the
accumulation of mtDNA mutations and deletions. In oocytes,
low levels of mitochondrial oxidative phosphorylation may occur
for up to 40 years before follicle maturation and ovulation, fur-
ther increasing the risk for mtDNA mutations. The result is the
increased rate of aneuploidy, especially trisomies, observed in the
offspring of older women. It also appears that oxidative phos-
phorylation and ATP production in the follicle is impaired in
older women. It has been demonstrated that embryo implant-
ation potential is correlated with the ATP content of the embryo
[19]. Preliminary data demonstrated that CoQ10 treatment, but
not ALA and resveratrol, was associated with increased oocyte
numbers and oocyte mitochondrial activity parameters, similar to
oocytes from young ICR controls [20]. On the contrary to ALA
administration alone, the combination of ALA and inositols not
only modulate insulin plasma levels but also, thanks to inositols,
improved the reproductive pathways thanks to an effect on FSH
signal transduction [7,11].
The role of alpha-lipoic acid in treatment of
endometriosis and vestibulodynia
Oxidative stress has been suggested in the etiology of chronic
pelvic pain [21]. 40–87%of women with chronic pelvic pain
have endometriosis [22]. Two studies [23,24] evaluated antioxi-
dant substances, among which the alpha lipoic acid, for the treat-
ment of endometriosis.
Agostins et al., tested the association of 1000 lg/mLN-Acetyl
Cysteine (NAC), 500 lg/mL ALA, and 50 lg/mL bromelain for
the treatment of endometriosis in vivo murine model and in vitro
model. They evaluated the compound mixture on SCID mice
whose peritoneal cavity was injected with human endometriotic
tissue. Treated mice grew a significant lower number of cyst
compared to untreated animals and larger cysts were observed in
untreated animals. They compared the expression of vascular cell
adhesion molecule-1 (VCAM1), that plays a critical role in regu-
lation of inflammatory process, on Endometriotic Endothelial
cells (EEC) untreated, stimulated for 12 h with TNF-a, and
treated withTNF-apreviously preincubated for 72 h with NAC,
ALA and Br, used alone or in association. They found a signifi-
cant decrease of VCAM1 levels only with the drug combination.
Finally, the authors observed that the NAC/LA/Br mixture was
able to induce a statistical significant (p<.05) increase of apop-
tosis of EECs. In conclusion, the NAC/ALA/Br association may
have potential therapeutic uses in the prevention and treatment
of patients with endometriosis [23].
Caruso et al. assessed the effect of the combination between
300 mg Palmitoylethanolamide (PEA) and 300 mg ALA on qual-
ity of life (QoL) and sexual function in 56 women with chronic
pelvic pain associated with endometriosis. They studied the
intensity of pelvic pain and evaluated QoL and the quality of sex-
ual activity. They did not find significant differences in QoL and
sexual activity during the first three months of treatment at the
6th and 9th month of drug assumption, reduction of chronic pel-
vic pain, dysmenorrhea and dyspareunia was significant, as well
as the improvement in all categories of QoL and the sexual func-
tion scores [24].
Finally one study evaluated the role of ALA plus omega-3
polyunsaturated fatty acids (n-3 PUFAs) in combination with
amitriptyline therapy in patients with vestibulodynia/painful
bladder syndrome (VBD/PBS). Eighty-four women were ran-
domly assigned to receive amitriptyline or amitriptyline plus LA
2C. DI TUCCI ET AL.
600 mg plus docosahexaenoic acid 250 mg and eicosapentaenoic
acid 16.67 mg for 12 weeks. After treatment, the reduction of
pain rating index and of the dyspareunia grade was of greater
statistical significance in the amitriptyline plus LA and n-3
PUFAs group [25].
Painful bladder syndrome and alpha lipoic acid
Interstitial cystitis (IC) is a chronic syndrome characterized by
symptoms of urinary urgency/frequency, pelvic pain, and nyctu-
ria in the absence of bacterial infection or any other identifiable
pathology [26]. Oral tricyclic antidepressants are commonly used
in the treatment of vulvar pain and painful bladder syndrome
(PBS)/IC, with amitriptyline used as a first-line agent. Murina
et al found out that the addition of ALA/n-3 PUFAs to amitrip-
tyline treatment in patients with painful bladder syndrome (PBS)
appears to improve outcomes and may allow for a lower dosage
of amitriptyline, which may lead to fewer adverse effects [25].
It has been observed that the urothelial expression of the che-
mokine fractalkine (CX3CL1) and its receptor (CX3CR1) is
markedly increased in a mouse model of chronic cystitis [27]. In
this regard, Yuridullah et al. demonstrated a robust upregulation
of both CXCL1 and CXCR1 in the urothelium following chronic
cyclophosphamide (CYP)-induced cystitis in the rat [27]. Because
CYP-induced cystitis closely resembles the features of interstitial
cystitis in humans [28], these observations establish downregula-
tion of fractalkine as a potential target for the therapy of this
common clinical entity. ALA has been demonstrated to act as an
effective agent to reduce fractalkine mRNA and protein expres-
sion as well as fractalkine-mediated inflammatory processes [29];
secondly, ALA has the capacity to inhibit TNFa-induced expres-
sion of fractalkine [30]. ALA could reverse the harmful effects of
high levels of oxidative stress in bladder inflamed tissue due to
its potent antioxidant activity [31]. Altogether these observations
suggest that ALA may represent a novel pharmacotherapeutic
strategy in the clinical management of interstitial cystitis.
Alpha-lipoic acid and miscarriage
Threatened miscarriage is a clinical pregnancy condiction that
occurs during the first 20 weeks in almost 20%of gestation.
Subchorionic hematoma is the cause of vaginal bleeding in 18%
of cases and may increase the risk of pregnancy loss in 46%by
immune and inflammatory condition [32,33]. Many cytokins are
involved in pathogenic mechanism of miscarriage. In humans
many clinical trials were performed to analyze the efficacy and
tolerability of ALA in pregnant women. Costantino et al con-
firmed the safety of the administration of 1200 mg once a day i.v.
or 600 mg once a day i.v. for 3 weeks followed by 600 mg three
times a day orally for 6 months in pregnant women [34].
The recent use of ALA in patients with threatened miscarriage
to improve the subchorionic hematoma resorption is a promising
area of researches and studies. During abortion, there is an eleva-
tion of TNFaIL2, TNFband IFcinduced by TH1 and also an
increase of pro inflammatory IL6 secreted by TH2.
Monastra et al in their work evaluated the action of ALA in
preventing miscarriage. ALA reduces pro-inflammatory cytokine
levels, such as TNF-a, IL-1b, IL-6, IL-8, IL-17 and INFc, while it
induces anti-inflammatory IL-10 release. Other molecules may be
involved in the mechanism of subchorionic hematoma resolution.
Vascular endothelial growth factor (VEGF) stimulates epitheliali-
zation and collagen deposition in wounds and Alpha-Smooth
Muscle Actin (alpha-SMA) takes part in fibrogenesis [35–37].
ALA may increase VEGF, as demonstrated in study conducted
on rats by Micili et al with enhance of wound healing in uterine
full thickness injury. In addition, inflammation is a useful mech-
anism for the implantation in physiologic pregnancy with an
increase of IL-17 released by Th17, but overexpression of IL-17
can harm embryo development. Treg cells instead are involved in
the immunoregulation and in the induction of tolerance [38].
ALA suppresses the number of Th17 and increases splenic Treg
cells [34,39].
Porcaro et al conducted a randomized controlled clinical trial
in pregnant women with threatened miscarriage to test the role of
ALA supplementation (600 mg by oral route) in improving the
standard treatment with progesterone vaginal suppositories, in
healing subchorionic hematomas and also in reducing vaginal
bleeding, abdominal pain, and uterine contractions. The group
treated with progesterone plus ALA had a better and faster evolu-
tion during the first 20 weeks of gestation. Signs of threatened
abortion decreased or disappeared in the group treated with ALA
plus progesterone, faster than in the group treated with progester-
one alone. There was a clinical evolution of uterine wound healing
and hematoma resorption in patients treated with ALA [40].
Costantino et al studied the administration of 400 mg of vagi-
nal Progesterone or 10 mg of vaginal ALA in 62 pregnant
women, in the first trimester of gestation with threatened miscar-
riage and subchorionic hematoma. In the ALA group, the sub-
chorionic hematoma was reabsorbed more quickly in comparison
with the progression detected in progesterone group. The num-
ber of miscarriages was smaller in the ALA group, compared to
progesterone group [41].
Alpha-lipoic acid and gestational diabetes
Maternal gestational diabetes (GDM) is known to increase the risk
of congenital malformation [42,43]. Some studies evaluated the
protective effect of lipoic acid (ALA) on fetal outcome of diabetic
mothers. Coughlan et al have studied placental tissue from women
with GDM and found out that in response to oxidative stress,
TNF alpha, 8-isoprostane release and nuclear factor-KB (NF-KB)
DNA- binding activity were significantly increased in normal tis-
sues (20-fold, 2-fold, and 35%,respectively,p<.01). Conversely,
there was not a significant increase in GDM placental tissues [44].
On the basis of this information, we hypothesize that the antioxi-
dative activity of LA might be effective in preventing diabetic
embryopathy. In fact, there have been different reports that sug-
gest the beneficial effect of ALA in preventing diabetic embryop-
athy in rats [45–47]. In particular Sugimura et al treated daily
with either ALA (100 mg/kg body weight) or saline between gesta-
tional days 0 and 18 pregnant diabetic or nondiabetic mice. ALA
treatment decreased the incidence of cardiovascular malformations
(CVMs) from 30 to 3%, of skeletal malformations from 29 to 6%,
of external malformations from 39%to 11%and of neural tube
defects (NTDs) from 30%to 8%[45]. An in vitro study conducted
on human umbilical vein endothelial cells (HUVECs) demon-
strates that both Centella asiatica (CA) and ALA, or a combination
thereof, are able to reduce the inflammatory response induced
congenital malformations, therefore, potentially dangerous on the
endothelium of chronic exposure to hyperglycemia in vivo [48].
Alpha-lipoic acid and premature rupture of
fetal membranes
Preterm birth is one of the major cause of neonatal mortality
and morbidity [49]. In one third of preterm births the triggering
GYNECOLOGICAL ENDOCRINOLOGY 3
event is constituted by preterm premature rupture of fetal mem-
branes (pPROM). It is hypothesized that fetal membranes are
weakened and ultimately ruptured as a result of collagen remod-
eling and apoptosis [50,51]. Tissue remodeling has been strongly
associated with production of reactive oxygen species (ROS) that
induce matrix metalloproteinase 9 (MMP9) and prostaglandins
[52]. Antioxidants have therefore been proposed as potential
inhibitors of premature fetal membrane remodeling and pre-
term rupture.
Moore et al., in 2009 [53] observed that ALA inhibits TNF-
induced weakening, decreasing MMP9 and PGE 2 release in cul-
tured in vitro fetal membranesand TNF and IL1B-induced
MMP9 release by cultured amnion epithelial cells.pPROM is
highly associated with decidual hemorrhage with resultant
thrombin production [54–57].
Moore et al., in 2010 [58] demonstrated that thrombin caused
fetal membranes weakness in vitro in a dose-dependent manner
and induced collagen remodeling in the amnion component of
the FM, by induction of MMP9 protein. The incubation of ALA
with FM fragments inhibited thrombin-induced FM weakening
and abolished the thrombin-induced increases of MMP9 in
amnion component.
Kumar et al., in 2011 confirmed that thrombin weakened iso-
lated AM in a dose-dependent manner. Pre-incubation with ALA
completely inhibited thrombin-induced AM weakening and
inhibited the thrombin-induced increase in MMP9 [59].
Conclusions
ALA is a promising antioxidant in gynecology. The first field of
application is the treatment of neuropatic pain and phase three
studies demonstrated the role of ALA in the treatment of disme-
norrea and vulvar pain.
Studies in patients with PCOS demonstrated an improvement
in amenorrhea and hyperandrogenism with beneficial effects on
fertility. The use of ALA on infertile patients was not tested in
phase three studies and other studies are necessary to assess the
role of this agent in the treatment of infertility.
The use of ALA as a dietary supplement during pregnancy
has risen greatly in recent years. Various studies were conducted
to explore not only its efficacy, but also its safety in the preven-
tion of pPROM and gestational diabetes, although further studies
are required to evaluate its tolerability.
With regard to dosage in humans, oral ALA supplementation
at doses of up to 2400 mg/day and intravenous administration of
600 mg/day did not seem to have any side effects [60]. These
studies were carried out mainly on animals or on small numbers
of patients, and this is their major drawback. Similar studies in
vivo, with a larger sample size, are necessary to confirm the bio-
logical significance of these findings. It is important to focus on
another drawback of ALA: its costs. We also noticed that in
almost all studies, ALA was always administered in combination
with other molecules. Therefore, in our opinion, further studies
are needed to evaluate its real benefits.
Disclosure statement
The authors report no conflict of interest.
ORCID
Chiara Di Tucci http://orcid.org/0000-0002-1292-9672
References
[1] Suh JH, Hong W, Rui-Ming L, et al. (R)-a-Lipoic acid reverses the
age-related loss in GSH redox status in post-mitotic tissues: evidence
for increased cysteine requirement for GSH synthesis. Arch Biochem
Biophys. 2004;423:126–135.
[2] Bast A, Haenen GR. Lipoic acid: a multifunctional antioxidant.
Biofactors. 2003;17:207–213.
[3] Spector A, Huang RR, Yan GZ, Wang RR. Thioredoxin fragment 31-
36 is reduced by dihydrolipoamide and reduces oxidized protein.
Biochem Biophys Res Commun. 1988;150:156–162.
[4] Masharani U, Gjerde C, Evans JL, et al. Effects of controlled-release
alpha lipoic acid in lean, nondiabetic patients with polycystic ovary
syndrome. J Diabetes Sci Technol. 2010;4:359–364.
[5] Cianci A, Panella M, Fichera M, et al. D-Chiro-Inositol and alpha
lipoic acid treatment of metabolic and menses disorders in women
with PCOS. Gynecol Endocrinol. 2015;31:483–486.
[6] Konrad D, Somwar R, Sweeney G, et al. The antihyperglycemic drug
alpha-lipoic acid stimulates glucose uptake via both Glut4 transloca-
tion and Glut4 activation: potential role of P38 mitogen-activated pro-
tein kinase in Glut4 activation. Diabetes. 2001;50:1464–1471.
[7] Genazzani AD, Despini G. Santagni S, et al. Effects of a combination
of alpha lipoic acid and myo-inositol on insulin dynamics in over-
weight/obese patients with PCOS. Endocrinol Metab Syndr.
2014;3(3):140. doi:10.4172/2161-1017.1000140.
[8] Cappelli V, Di Sabatino A, Musacchio MC, De Leo V. Evaluation of
a new association between insulin-sensitizers and alpha-lipoic acid
in obese women affected by PCOS. Minerva Ginecol. 2013;65:
425–434.
[9] Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-
lipoic acid on oocyte quality in polycystic ovary syndrome non-obese
women undergoing in vitro fertilization: a pilot study. J Biol Regul
Homeost Agents. 2015;29:913–924.
[10] Morgante G, Cappelli V, Di Sabatino A, et al. Polycystic Ovary
Syndrome (PCOS) and hyperandrogenism: the role of a new natural
association. Minerva Ginecol. 2015;67:457–663.
[11] Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of
alpha-lipoic acid (ALA) administration on insulin sensitivity in obese
PCOS patients. J Endocrinol Invest. 2018;41(5):583–590.
[12] Pasqualotto EB, Agarwal A, Sharma RK, et al. Effect of oxidative
stress in follicular fluid on the outcome of assisted reproductive pro-
cedures. Fertil Steril. 2004;81:973–976.
[13] Luvoni GC, Keskintepe L, Brackett BG. Improvement in bovine
embryo production in vitro by glutathione-containing culture media.
Mol Reprod Dev. 1996;43:437–443.
[14] Taylor CT. Antioxidants and reactive oxygen species in human fertil-
ity. Environ Toxicol Pharmacol. 2001;10:189–198.
[15] Talebi A, Zavareh S, Kashani MH, et al. The effect of alpha lipoic
acid on the developmental competence of mouse isolated preantral
follicles. J Assist Reprod Genet. 2012;29:175–183.
[16] Zavareh S, Rahnama A, Karimi I, Salehnia M. Effect of in vitro mat-
uration technique and alpha lipoic acid supplementation on oocyte
maturation rate: focus on oxidative status of oocytes. Int J Fertil
Steril. 2016;9:442–451.
[17] Avci B, Bahadir A, Tuncel OK, Bilgici B. Influence of A-Tocopherol
and A-Lipoic acid on bisphenol-A-Induced oxidative damage in liver
and ovarian tissue of rats. Toxicol Ind Health. 2016;32:1381–1390.
[18] Hasselberg L, Meier S, Svardal A. Effects of alkylphenols on redox
status in first spawning atlantic cod (Gadus Morhua). Aquat Toxicol.
2004;69:95–105.
[19] Takeuchi T, Neri QV, Katagiri Y, et al. Effect of treating induced
mitochondrial damage on embryonic development and epigenesis.
Biol Reprod. 2005;72:584–592.
[20] Bentov Y, Esfandiari N, Burstein E, Casper RF. The use of mitochon-
drial nutrients to improve the outcome of infertility treatment in
older patients. Fertil Steril. 2010;93:272–275.
[21] Shahed AR, Shoskes DA. Oxidative stress in prostatic fluid of patients
with chronic pelvic pain syndrome: correlation with gram positive
bacterial growth and treatment response. J Androl. 2000;21:669–675.
[22] Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: trans-
lational evidence of the relationship and implications. Hum Reprod
Update. 2011;17:327–346.
[23] Agostinis C, De Leo R, Zauli G, et al. The combination of N-acetyl
cysteine, alpha-lipoic acid, and bromelain shows high anti-inflamma-
tory properties in novel in vivo and in vitro models of endometriosis.
Mediators Inflam. 2015;2015:918089. doi: 10.1155/2015/918089.
4C. DI TUCCI ET AL.
[24] Caruso S, Iraci Sareri M, Casella E, et al. Chronic pelvic pain, quality
of life and sexual health of women treated with palmitoylethanola-
mide and a-Lipoic acid. Minerva Ginecol. 2015;67:413–419.
[25] Murina F, Graziottin A, Felice R, Gambini D. Alpha lipoic acid plus
omega-3 fatty acids for vestibulodynia associated with painful bladder
syndrome. J Obstet Gynaecol Can. 2017;39:131–137.
[26] Butrick CW. Interstitial cystitis and chronic pelvic pain: new insights
in neuropathology, diagnosis, and treatment. Clin Obstet Gynecol.
2003;46:811–823.
[27] Yuridullah R, Corrow KA, Malley SE, Vizzard MA. Expression of
fractalkine and fractalkine receptor in urinary bladder after cyclophos-
phamide (cyp)-induced cystitis. Auton Neurosci. 2006;126:380.
[28] Sand PK. Proposed pathogenesis of painful bladder syndrome/intersti-
tial cystitis. J Reprod Med. 2006;51(3 Suppl):234–240.
[29] Bilska A, Włodek L. Lipoic acid –the drug of the future? Pharmacol
Rep. 2005;57:570–577.
[30] Lee KM, Park KG, Kim YD, et al. Alpha-lipoic acid inhibits fractal-
kine expression and prevents neointimal hyperplasia after balloon
injury in rat carotid artery. Atherosclerosis. 2006;189:106–114.
[31] Sung MJ, Kim W, Ahn SY, et al. Protective effect of alpha-lipoic acid
in lipopolysaccharide-induced endothelial fractalkine expression. Circ
Res. 2005;97:880–890.
[32] Nagy S, Bush M, Stone J, et al. Clinical significance of subchorionic
and retroplacental hematomas detected in the first trimester of preg-
nancy. Obstet Gynecol. 2003;102:94–100.
[33] Leite J, Ross P, Rossi AC, Jeanty P. Prognosis of very large first-tri-
mester hematomas. J Ultrasound Med. 2006;25:1441–1445.
[34] Wang KC, Tsai CP, Lee CL, et al. a-Lipoic acid enhances endogenous
peroxisome-proliferator-activated receptor-Cto ameliorate experimen-
tal autoimmune encephalomyelitis in mice. Clin Sci (Sci.
2013;125:329–340.
[35] Monastra G, De Grazia S, Cilaker Micili S, et al. Immunomodulatory
activities of alpha lipoic acid with a special focus on its efficacy in
preventing miscarriage. Expert Opin Drug Deliv. 2016;13:1695–1708.
[36] Bao P, Kodra A, Tomic-Canic M, et al. The role of vascular endothe-
lial growth factor in wound healing. J Surg Res. 2009;153:347–358.
[37] Cherng S, Young J, Ma H. Alpha-smooth muscleactin (a-SMA). J Am
Sci. 2008;4:7–9.
[38] Micili SC, Goker A, Sayin O, et al. The effect of lipoic acid on wound
healing in a full thickness uterine injury model in rats. J Mol Hist.
2013;44:339–345.
[39] Marracci GH, Jones RE, McKeon GP, Bourdette DN. Alpha
Lipoic Acid Inhibits T Cell Migration into the Spinal Cord and
Suppresses and Treats Experimental Autoimmune Encephalomyelitis.
J Neuroimmunol. 2002;131:104–114.
[40] Porcaro G, Brillo E, Giardina I, Di IR. Alpha Lipoic Acid (ALA)
effects on subchorionic hematoma: preliminary clinical results. Eur
Rev Med Pharmacol Sci. 2015;19(18):3426–3432.
[41] Costantino M, Guaraldi C, Costantino D. Resolution of subchorionic
hematoma and symptoms of threatened miscarriage using vaginal
alpha lipoic acid or progesterone: clinical evidences. Eur Rev Med
Pharmacol Sci. 2016;20:1656–1663.
[42] Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus
during pregnancy and the risks for specific birth defects: a popula-
tion-based case-control study. Pediatrics. 1990;85:1–9.
[43] Kousseff BG. Diabetic embryopathy. Curr Opin Pediatr. 1999;11:
348–352.
[44] Coughlan MT, Permezel M, Georgiou HM, Rice GE. Repression of
oxidant-induced nuclear factor-kappab activity mediates placental
cytokine responses in gestational diabetes. J Clin Endocrinol Metab.
2004;89:3585–3594.
[45] Sugimura Y, Murase T, Oyama K, et al. Prevention of neural tube
defects by loss of function of inducible nitric oxide synthase in fetuses
of a mouse model of streptozotocin-induced diabetes. Diabetologia.
2009;52:962–971.
[46] Wiznitzer A, Ayalon N, Hershkovitz R, et al. Lipoic acid prevention
of neural tube defects in offspring of rats with streptozocin-induced
diabetes. Am J Obstet Gynecol. 1999;180:188–193.
[47] Al Ghafli MH, Padmanabhan R, Kataya HH, Berg B. Effects of alpha-
lipoic acid supplementation on maternal diabetes-induced growth
retardation and congenital anomalies in rat fetuses. Mol Cell
Biochem. 2004;261:123–135.
[48] Di Tomo P, Di Silvestre S, Cordone VGP, et al. Centella asiatica and
lipoic acid, or a combination thereof, inhibit monocyte adhesion to
endothelial cells from umbilical cords of gestational diabetic women.
Nutr Metab Cardiovasc Dis. 2015;25:659–666.
[49] National Institute for Health and Care Excellence. Preterm Labour
(New guidelines 25) 2015; https://www.nice.org.uk/guidance/ng25/
resources/preterm-labour-and-birth-pdf-1837333576645
[50] Moore RM, Mansour JM, Redline RW, et al. The physiology of fetal
membrane rupture: insight gained from the determination of physical
properties. Placenta. 2006;27:1037–1051.
[51] Menon R, Fortunato SJ. The role of matrix degrading enzymes and
apoptosis in rupture of membranes. J Soc Gynecol Investig.
2004;11:427–437.
[52] Lappas M, Permezel M, Rice GE. N-Acetyl-Cysteine inhibits phospho-
lipid metabolism, proinflammatory cytokine release, protease activity,
and nuclear factor-kappab deoxyribonucleic acid-binding activity in
human fetal membranes in vitro. J Clin Endocrinol Metab.
2003;88:1723–1729.
[53] Moore RM, Novak JB, Kumar D, et al. Alpha-lipoic acid inhibits
tumor necrosis factor-induced remodeling and weakening of human
fetal membranes. Biol Reprod. 2009;80:781–787.
[54] Harger JH, Hsing AW, Tuomala RE, et al. Risk factors for preterm
rupture of fetal membranes: a multicenter case-control study. Am J
Obstet Gynecol. 1990;163:130–137.
[55] Rosen T, Kuczynski E, O’Neill LM, et al. Plasma levels of thrombin-
antithrombin complexes predict preterm premature rupture of the
fetal membranes. J Matern Fetal Neonatal Med. 2001;10:297–300.
[56] Chaiworapongsa T, Espinoza J, Yoshimatsu J, et al. Activation of
coagulation system in preterm labor and preterm premature rupture
of membranes. J Matern Fetal Neonatal Med. 2009;11:368–373.
[57] Elovitz MA, Baron J, Phillippe M. The role of thrombin in preterm
parturition. Am J Obstet Gynecol. 2001;185:1059–1063.
[58] Moore RM, Schatz F, Kumar D, et al. Alpha-lipoic acid inhibits
thrombin-induced fetal membrane weakening in vitro. Placenta.
2010;31:886–892.
[59] Kumar D, Schatz F, Moore RM, et al. The effects of thrombin and
cytokines upon the biomechanics and remodeling of isolated amnion
membrane, in vitro. Placenta. 2011;32:206–213.
[60] Goraca A, Huk-Kolega H, Piechota A, et al. Lipoic acid –biological
activity and therapeutic potential. Pharmacol Rep. 2011;63:849–858.
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