Basic Science – Review Article

Med Cannabis Cannabinoids 2019;2:14–21 Received: November 27, 2018

Accepted: February 25, 2019
DOI: 10.1159/000499164 Published online: May 24, 2019

Cannabinoids in Gynecological Diseases

Petra Luschnig Rudolf Schicho
Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria

Keywords Cannabinoids and the Endocannabinoid System

Endocannabinoid system · Cannabinoid receptors ·
Endometriosis · Cervical cancer · TRPV1 Cannabinoids: Endo-, Phyto-, and Synthetic
Cannabinoids
Since its first description as a multifunctional system 2
Abstract decades ago, the endocannabinoid system (ECS) has
The endocannabinoid system (ECS) is a multifunctional ho­ gained a lot of interest [1]. The ECS comprises enzymes,
meostatic system involved in many physiological and patho­ cannabinoid receptors and their related receptors, and li-
logical conditions. The ligands of the ECS are the endo­ gands, i.e., the endocannabinoids (eCB), which are syn-
cannabinoids, whose actions are mimicked by exogenous thesized endogenously. Phytocannabinoids (pCB) that
cannabinoids, such as phytocannabinoids and synthetic are isolated from Cannabis sativa and synthetic cannabi-
cannabinoids. Responses to the ligands of the ECS are medi­ noids (sCB) affect the receptors of the ECS as exogenous
ated by numerous receptors like the classical cannabinoid cannabinoids.
receptors (CB1 and CB2) as well as ECS-related receptors, e.g., The first eCB that were discovered were N-arachi-
G protein-coupled receptors 18 and 55 (GPR18 and GPR55), donoyl-ethanolamine, better known as anandamide
transient receptor potential ion channels, and nuclear per­ (AEA), and 2-arachidonoylglycerol (2-AG) [2–4]. Fur-
oxisome proliferator-activated receptors. The ECS regulates ther endogenous ligands of the ECS are 2-AG ether (no-
almost all levels of female reproduction, starting with oocyte ladin ether), N-arachidonoyl dopamine, and O-arachi-
production through to parturition. Dysregulation of the ECS donoyl ethanolamine (virodhamine) [5–7]. The best in-
is associated with the development of gynecological disor­ vestigated eCB are AEA and 2-AG, which are produced
ders from fertility disorders to cancer. Cannabinoids that act “on demand”. They are triggered by a stimulus that leads
at the ECS as specific agonists or antagonists may potential­ to an increase in the intracellular Ca2+ concentration and
ly influence dysregulation and, therefore, represent new cleavage of precursor molecules [6, 7]. Synthesis of eCB
therapeutic options for the therapy of gynecological disor­ take place in several tissues and cell types where they are
ders. © 2019 The Author(s)
Published by S. Karger AG, Basel P.L. and R.S. contributed equally to this paper.

© 2019 The Author(s) Rudolf Schicho

Published by S. Karger AG, Basel Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz
Universitätsplatz 4/I
E-Mail [email protected] This article is licensed under the Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International License (CC BY- AT–8010 Graz (Austria)
www.karger.com/mca E-Mail rudolf.schicho @ medunigraz.at
NC-ND) (http://www.karger.com/Services/OpenAccessLicense).
Usage and distribution for commercial purposes as well as any dis-
tribution of modified material requires written permission.
catalyzed by specific synthases, such as N-acylphosphati- ferent groups in the last few years that GPR55 is involved
dylethanolamine-hydrolyzing phospholipase D (NAPE- in cancer cell proliferation in vitro and/or in vivo in vari-
PLD) and others [8]. After release, inactivation of AEA ous types of cancers including ovarian, prostate, and skin
and 2-AG occurs promptly by enzymatic hydrolysis of the cancer as well as non-small lung cancer [34–38].
amide and ester bonds by fatty acid amide hydrolase PPAR represent a family of nuclear hormone receptors
(FAAH) and monoacylglycerol lipase (MAGL) [9–13]. consisting of 3 isoforms (α, δ, and γ [39]), and they are
More than a 100 pCB have been identified, of which expressed in many organs including the ovaries, uterus,
the psychotropic (–)-trans-Δ9-tetrahydrocannabidiol and prostate [40–42]. Numerous functions have been at-
(THC) and the nonpsychotropic (–)-cannabidiol (CBD) tributed to these receptors including the regulation of
are the best studied [14–16]. THC and CBD mediate a metabolism and energy homeostasis, cell proliferation,
broad spectrum of biological actions including analgesic, and inflammation [43–45]. These effects are mediated by
antiemetic, and anti-inflammatory effects [12–14]. a multitude of endogenous and exogenous ligands, e.g.,
eicosanoids or plant extracts [46, 47]. Within the last 2
Classical Cannabinoid Receptors decades, researchers have shown that cannabinoids (i.e.,
Responses to eCB, but also to pCB and sCB, are medi- eCB, pCB, and sCB) mediate anti-inflammatory and an-
ated by numerous receptors of which cannabinoid recep- tiemetic effects also via PPARα and PPARγ receptors
tor type 1 (CB1) and cannabinoid receptor type 2 (CB2) [48–53].
represent the classical cannabinoid receptors. CB1 and The TRP channel superfamily responds to many
CB2 are G-protein-coupled receptors and they are in- physical and chemical stimuli, including cannabinoids
volved in many (patho-) physiological processes such as [54]. TRP channels that cause proliferative effects belong
pain, inflammation, cancer, and hypertension as well as to the 3 major subfamilies of these channels, i.e., the
neurodegenerative disorders [15]. The expression of the TRPC (canonical), the TRPV (vanilloid), and the TRPM
CB1 receptor in the brain is responsible for the psychotro- (melastatin) channels [55]. Within the members of these
pic effects of THC and other synthetic CB1 agonists. CB1 subfamilies the TRPV6 channel is the best studied. A
expression has also been found in peripheral organs like high expression of TRPV6 has been found in many types
the heart, spleen, and endocrine glands as well as in parts of cancers, such as colon, thyroid, prostate, and ovarian
of the male and female reproductive systems and the uri- cancer [56–61]. The TRPC6 channel of the TRPC sub-
nary tract, including the ovaries, uterus, testis, prostate, family and some members of the TRPM subfamily have
and placenta [16–19]. The second classical cannabinoid been shown to be related to procarcinogenic effects in
receptor, CB2, is expressed only to a minor degree in the prostate, cervical, ovarian, breast, and gastric cancers
nervous system. It is mainly located in tissues of the im- [62–67].
mune system including the spleen, tonsils, thymus, and
bone marrow as wells as in immune cells such as B cells, (Patho-) Physiological Impact of the ECS
natural killer cells, monocytes, neutrophils, and CD8+ A variety of physiological and pathological processes
and CD4+ T cells [20–22]. throughout the organism are affected by the ECS includ-
ing modulation of neuronal functions, microcirculation,
ECS-Related Receptors and functions of immune cells [68]. Hence, the ECS takes
Besides CB1 and CB2, many other cannabinoid-sensi- part in the modulation of pain and inflammation and
tive receptors exist that can be designated as ECS-related may be also involved in regulatory processes during car-
receptors. Several studies have emphasized their relation- cinogenesis [69–75]. Ligands of the ECS could act via
ship with the ECS [23–25]. The metabotropic G-protein- cannabinoid receptors as well as via ECS-related recep-
coupled receptors GPR55, GPR18, and GPR119 have tors. The receptors represent therapeutic opportunities
been demonstrated to be targets of eCB, but also of pCB in the treatment of pain, inflammation, and chemother-
and sCB, but they have not been categorized as cannabi- apy-induced nausea or vomiting since they cause inhibi-
noid receptors by the International Union of Pharmacol- tory effects in these pathological processes [76]. Aside
ogy [25–29]. Other families of ECS-related receptors are from that, modulation of the ECS by natural and syn-
the nuclear peroxisome proliferator-activated receptors thetic ligands may also result in the induction of apopto-
(PPAR) and the transient receptor potential (TRP) ion sis, inhibition of cancer cell invasion, and neoangiogen-
channels [30–33]. The GPR55 receptor plays an impor- esis [77–81].
tant role in cancer cell behavior. It has been shown by dif-

Cannabinoids in Gynecological Diseases Med Cannabis Cannabinoids 2019;2:14–21 15

DOI: 10.1159/000499164
 The ECS in Gynecological Disorders and Cancer ECS represents a big field of research for the development
of new therapeutic tools in the management of this disor-
Since the ECS is involved in almost all levels of female der. Sanchez et al. [99] recently reported elevated plasma
reproduction, i.e., from oocyte production to parturition, levels of AEA and 2-AG in women with endometriosis.
several studies in recent years have shown that dysregula- There were, however, no changes in CB1 expression in
tion of the ECS is associated with the development of dis- endometrial stromal cells during the menstrual cycle of
orders of the female reproductive tract [82–90]. These in- the women with endometriosis, although in the healthy
clude fertility disorders like polycystic ovary syndrome controls (and in contrast to findings by Bilgic et al. [100])
(PCOS), endometriosis, and gynecological cancers [91– an upregulation of CB1 was found in the S-phase [99].
93]. TRPV1, an ECS-related receptor, was found to be ex-
pressed at comparable levels in ectopic endometrial stro-
Cannabinoids and PCOS mal cells from both healthy controls and women with en-
PCOS is a metabolic and endocrinal disorder. Its dometriosis [99]. These findings are in accordance with
pathogenesis was only recently connected to the ECS by previously published studies showing TRPV1 expression
demonstrating that levels of AEA and 2-AG were elevated in ectopic endometrial epithelial cells [101]. The presence
in peripheral blood mononuclear cells of women with of this receptor in endometrial tissue and the elevated lev-
PCOS [94]. Recently, Cui et al. [95, 96] found reduced els of eCB in patients with endometriosis may therefore
FAAH expression in the endometrium of patients with be associated with the development of chronic inflamma-
PCOS and an increase in AEA plasma levels, as FAAH is tory pain [99].
mainly involved in AEA degradation. Previous studies Besides the discovery of new treatment targets for pain
have shown that elevated plasma AEA levels in connec- management, there is still the need to know how ectopic
tion with a lower FAAH activity resulted in ectopic preg- lesions develop and proliferate. By immunostaining of
nancy which is also linked to PCOS [85, 97]. Thus, it CB1 and CB2 in endometriotic and normal tissue, Bilgic et
seems likely that a dysregulation of the ECS is involved in al. [100] showed that the expression of both receptors was
pregnancy complications of women with PCOS. reduced in the glandular epithelial and stromal cells of
Apart from high eCB levels, insulin resistance is com- women with endometriosis. This is in agreement with
mon in the pathophysiology of PCOS, often causing he- findings by Resuehr et al. [88], who observed reduced im-
patic stress and liver damage, which ends up in elevated munostaining of CB1 in patients with endometriosis [88,
levels of alanine aminotransferase, a marker of hepatocel- 100]. Moreover, it was demonstrated that the selective CB1
lular injury. Dawson et al. [91] recently reported that a agonist ACPA as well as the selective CB2 agonist CB 65
weight-reducing therapy with the CB1 antagonist induced apoptosis and reduced proliferation of Ishikawa
rimonabant in obese women with PCOS resulted in a re- cells (normal endometrial glandular cells) and the endo-
duction of alanine aminotransferase, accompanied by a metriosis cyst wall cells CRL-7566 [100]. The CB2-medi-
reduction of insulin resistance. In contrast, it has been ated effect was more prominent in Ishikawa cells while the
reported that the amount of both vascular endothelial CB1-mediated effect was more prominent in CLR-7566
growth factor and interleukin-8, which play a crucial role cells [100]. Similar results were presented earlier by Lecon-
in inflammation, are paradoxically increased upon te et al. [102], who demonstrated an antiproliferative ef-
rimonabant treatment of obese women with POCS, which fect of the nonselective CB1/CB2 agonist WIN 55212-2 on
may compensate the benefit associated with weight loss deep infiltrating endometrial stromal cells. This effect was
[98]. More data are, therefore, needed to clarify the im- a result of inactivation of the Akt pathway by WIN 55212-
pact of the ECS in the pathogenesis of PCOS and whether 2 [102]. These in vitro results were confirmed by a mouse
a CB1 antagonist may be of benefit. model of deep infiltrating endometriosis [102]. In con-
trast, Sanchez et al. [103] found that selective activation of
Cannabinoids and Endometriosis CB1 by methanandamide was linked to the development
Endometriosis is a disease characterized by ectopic of ectopic lesions in a mouse model of endometriosis. The
growth of uterine endometrial tissue and it is usually as- discrepancies may be explained by the fact that there are
sociated with severe pain. Since the mechanisms for en- basic differences in the animal models of endometriosis.
dometriosis-related pain can be divided into 3 categories Sanchez et al. [103] used a model to elucidate the develop-
(nociceptive, inflammatory, and neuropathic), each of ment of ectopic lesions in initial stages while Leconte et al.
which is linked to the ECS, it is not surprising that the [102] transplanted human endometriotic tissue into nude

16 Med Cannabis Cannabinoids 2019;2:14–21 Luschnig/Schicho

DOI: 10.1159/000499164
mice to investigate effects on already established lesions. by immunohistochemical methods. Additionally, they
Thus, species differences between the rodent and human found AEA in the follicular fluid after ovarian stimulation
endometrium may exist [102, 103]. Certainly, more re- by hormones (following an in vitro fertilization protocol
search is necessary to identify potential new targets for which caused an increase in follicle size), suggesting that
therapy of endometriosis. AEA is involved in the maturation of follicles and oocytes
[82, 108]. Another study group demonstrated expression
Cannabinoids and Cervical Cancer of CB1 and FAAH in the ovarian surface epithelium from
Cervical cancer is the second leading cause of cancer which ovarian cancers originate, which could be another
in women and, due to the lack of effective treatment, hint for a possible involvement of the ECS in ovarian can-
more than 250,000 deaths are reported annually [104]. A cer [109]. The 2-AG degrading enzyme MAGL has been
possible influence of the ECS in the development of cervi- shown to be upregulated in aggressive human ovary can-
cal cancer has been elucidated in recent years. Contassot cer cells [110]. MAGL seems to be involved in oncogenic
et al. [89] reported a strong expression pattern of CB1 and signaling and hence in increased migration, invasion, and
CB2 as well as TRPV1 in cervical carcinoma cell lines and survival of cancer cells. This was also demonstrated by
biopsies. On top of that, it was shown that AEA had pro- MAGL overexpression in nonaggressive cancer cells
apoptotic effects on cervical carcinoma cell lines (HeLa which subsequently exhibited an increased pathogenic
and Caski) [89], which were not inhibited but rather en- phenotype [110]. Moreover, the application of an MAGL
hanced by CB1 and CB2 antagonists. On the other hand, inhibitor led to a reversion of the enhanced pathogenicity
the TRPV1 selective antagonist capsazepine protected the [110]. Regarding the expression of CB1 in ovarian cancer,
cell lines from AEA-induced apoptosis, indicating an im- Messalli et al. [111] revealed, by using immunohisto-
portant role of the TRPV1 channel in the proapoptotic chemistry, that CB1 expression was moderate in benign
action of AEA [89]. Additionally, it was demonstrated by and borderline epithelial ovarian tumors, but the expres-
Ramer et al. [105] that CBD is able to decrease the inva- sion was strongly increased in invasive ovarian tumors.
siveness of cancer cells in a concentration-dependent These findings suggest a correlation between the expres-
manner. The effect was observed in the cervical cancer sion patterns of ECS components and the prognosis for
cell lines HeLa and C33A as well as in the lung cancer cell ovarian cancer malignancy [111].
line A549 and seemed to be mediated by the upregulation It also turned out that the amount of lysophospholipids
of TIMP-1 via CB1/CB2 and TRPV1. The activation of in blood and ascites fluids was elevated in ovarian cancer
p38 and p42/44 mitogen-activated protein kinases was patients compared to healthy controls, a finding associated
identified as an upstream event of TIMP-1 upregulation with proliferation and the metastatic potential of ovarian
[105]. In agreement with these findings, it was reported cancer cells [112]. Hofman et al. [38] more recently de-
that treatment of different cervical cancer cell lines (HeLs, scribed that the elevation of lysophosphatidylinositol (an
SiHa, ME-180) with CBD led to a decrease of cell prolif- endogenous GPR55 agonist) in the ovarian cancer cell lines
eration [106]. Furthermore, CBD induced cell death by OVCAR-3, OVCAR-5, and COV-362 resulted in a GPR55-
the accumulation of cells in the sub-G0 phase (cell death dependent angiogenesis because pharmacological inhibi-
phase) of the cell cycle, a finding that was most likely cas- tion and genetic deletion of GPR55 reduced the proangio-
pase dependent because caspase-9 as well as caspase-3 genic potential of lysophosphatidylinositol in these cell
were upregulated upon CBD treatment [106]. Hence, lines. Additionally, they demonstrated that the mitogen-
CBD may be an additional therapeutic tool for the treat- activated protein kinase pathway was activated via GPR55
ment of cervical cancer, but in vivo studies will be needed by phosphorylation of ERK1/2 and p38, which are signal-
to exactly clarify the impact of CBD on cervical cancer. ing molecules known to be involved in proliferative and
migratory responses [38]. Thus, the involvement of the
Cannabinoids and Ovarian Cancer ECS in ovarian cancer may fuel expectations on new ther-
Among gynecological cancers, ovarian cancer is re- apeutics to combat this type of cancer.
sponsible for the highest mortality rate [107]. To deter-
mine a possible role of the ECS in the pathophysiology of Cannabinoids and Endometrial Cancer
the ovaries, El-Talatini et al. [82] studied the expression Endometrial cancer can be classified into type I and II
levels of different components of the ECS [108]. They tumors. Depending on the disease stage, various thera-
were able to show the expression of CB1 and CB2 as well pies exist, but the prognosis is still poor because of tumor
as of NAPE-PLD and FAAH in normal human ovaries recurrence [113]. Guida et al. [114] reported an upregula-

Cannabinoids in Gynecological Diseases Med Cannabis Cannabinoids 2019;2:14–21 17

DOI: 10.1159/000499164
tion of CB2 in endometrial cancer, whereby immuno­ Conclusions
staining was only successful in transformed malignant
cells and completely absent in normal endometrial tissue. A pivotal effect of the ECS in gynecological disorders
Furthermore, 2-AG levels were increased but MAGL ex- and cancers was demonstrated by various working groups
pression was decreased in comparison to controls, while in recent years. In particular, the development, progres-
AEA levels and FAAH expression were unaffected [114]. sion and prognosis of female urogenital diseases seem to
In accordance with these findings, Jové et al. [115] dem- be associated with dysregulation of the ECS. Due to its
onstrated that CB2 was expressed at higher levels in stag- regulatory functions, the ECS represents an important
es III and IV of endometrial carcinoma, which has been therapeutic target to be elucidated. Cannabinoids, espe-
linked to a poor prognosis. Contrary to Guida et al. [114], cially pCB or sCB, that manipulate the ECS as specific
they found an increase in CB1 expression by immunohis- agonists or antagonists may potentially influence dysreg-
tochemistry in endometrial carcinoma tissue compared ulation. For this reason, more research is required to shed
to normal endometrial tissue [115]. light on the complex interactions of the ECS in order to
The effects of pCB, such as THC, on endometrial can- find new therapeutic tools for therapy of gynecological
cer progression was recently evaluated by Zhang et al. disorders and cancer.
[116]. They found that THC inhibited endometrial can-
cer cell proliferation and migration by a decreased ex-
pression of matrix metalloproteinase-9 but not matrix Acknowledgement
metalloproteinase-2. The same effects could be detected
R.S. is supported by the Austrian Science Fund (FWF grants
after matrix metalloproteinase-9 silencing [116]. More
P30144 and KLI521-B31).
recently, the involvement of THC and CBD in endome-
trial cancer was investigated in 2 model cell lines, i.e.,
Ishikawa and Hec50co cells [117]. Expression of all com- Statement of Ethics
ponents of the ECS, including TRPV1, was detected in the
cells. Additionally, treatment of the cells with AEA or The authors have no ethical conflicts to disclose.
CBD (>5 µM) resulted in a reduced cell viability that was
linked to an increase in ROS production and caspase-3/-7
activity [117]. The findings regarding the proapoptotic Disclosure Statement
action of AEA are well in accordance with the observa-
tions by Contassot et al. [89], who described AEA-driven The authors have no conflict of interests to declare.
cancer cell apoptosis via TRPV1 activation.

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