Key words
curcumin - turmeric - health - ovary - proliferation - apoptosis - hormone - fecundity
Introduction
Curcuma/turmeric is a popular spice. Its health-promoting effects have already been
described in several reviews [1], [2], [3], [4], [5]. On the other hand, only one publication [6] reviewed curcuma action on reproductive processes, though it was focused on cancerogenesis
and not on curcuma action on a healthy reproductive system. The present publication
is the first attempt at summarizing the available information concerning the action
of curcuma and its constituents on a healthy female reproductive system, as well as
of the data concerning their ability to prevent and to treat reproductive disorders.
A search of the literature was performed in agreement with PRISMA-ScR criteria [7]. To find related articles, Pubmed, Web of Science, and SCOPUS databases were searched
for articles published between the years 2000 and 2021. In cases of repeated or conflicting
information or references, the most recent source was used. Words used in the search
were curcumin, turmeric, review, health, metabolism, fertility, ovarian, and mechanisms.
Provenance and Properties
Provenance and Properties
The herbs that belong to the genus Curcuma (Zingiberaceae) are currently cultivated in tropical and subtropical areas of Asia,
Australia, and South America. Approximately 93 – 100 species of Curcuma are described now. These herbs are widely used for the coloring and flavoring of
food, for preparation of food additives (the most known is curry powder), dyes, perfumes,
and cosmetics as well as in folk medicine. The most known and useful Curcuma species are Curcuma longa (Indian turmeric) and Curcuma zedoaria (zedoary). Turmeric is native to Southeast Asia but is now cultivated extensively
worldwide. Zedoary originated from India and Indonesia but it is cultivated in many
subtropical regions around the world. The rhizome is the most commonly used part of
these plants.
Turmeric rhizome typically contains carbohydrates (69.4%), protein (6.3%), fat (5.1%),
and minerals (3.5%). The main active components of the rhizome are the non-volatile
curcuminoids and the volatile oil [3]. A main biologically active component of C. longa L. is curcumoids curcumin, which is chemically known as diferuloylmethane [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-eptadiene-3,5-dione],
and its polyphenolic derivatives and metabolites, demethoxycurcumin and bisdemethoxycurcumin
[1]. The major components of curcuma oils are sesquiterpenoids and monoterpenoids [3], [4].
Mechanisms of Action
Curcumin has antioxidant, anti-inflammatory, antimicrobial, proapoptotic, antiproliferative,
antiangiogenic, and antimutagenic activities [2], [4], [8], [9], [10], which determine its physiological and therapeutic effects. For example, the antioxidant
action of curcumin defines its ability to prevent oxidative stress, DNA, and protein
damage [10]. Common molecular intracellular targets and mediators of curcuma action could be
cytokines and transcription factors promoting inflammatory processes, some protein
kinases, and enzymes. Curcumin can affect a number of signaling molecules like Nrf2,
β-catenin, NF-κB, p38 MAPK, DNA (cytosine-5)-methyltransferase-1, COX-2, TNF-α, 5-lipoxygenase, PGE2, FOXO3, generation nitric oxide and reactive oxygen species,
cyclin D1, VEGF, glutathione,
cytosolic PLA2, and p-Tau (p-τ). For example, curcumin can suppress inflammatory
processes through the downregulation of intracellular promoters of inflammation such
as Nrf2, NF-κB, STAT3, reactive oxygen species, and COX-2 (see [2] for review). On the other hand, curcumin can boost the functions of immunocompetent
cells, the production of inflammatory cytokines, and reparative processes [11], [12]. Furthermore, curcumin can suppress cancerogenesis [10], [13] and other illnesses [14] targeting microRNAs and long non-coding RNAs. The physiological action of turmeric
oils could be explained by their ability to inhibit reactive oxygen species, COX-2,
and other signaling molecules as well [3]. This ability of turmeric molecules to modulate many extra- and intracellular
signaling pathways related to various dysfunctions and diseases suggests that
it is a polyphenol with many targets and physiological and medicinal actions [2], [4].
Physiological and Therapeutic Actions
Physiological and Therapeutic Actions
The current literature describes anti-inflammatory, antioxidant, anticancer, antimutagenic,
antimicrobial, anti-obesity, hypolipidemic, cardioprotective, wound healing, and neuroprotective
properties of curcumin [4], [5], [11], [15]. Curcumin-containing Curcumas are popular in Asian folk medicine to treat pneumonia, bronchitis, leucorrhea, diarrhea,
dysentery, infectious wounds or abscesses, and insect bites. In this context, curcumin
is applicable as a carminative, digestive aid, stomachic, anthelmintic, appetizer,
tonic, and laxative. It is also used as a treatment against fever, gastritis, dysentery,
infections, hypercholesterolemia, hypertension, chest congestion, arthritis, jaundice,
liver and gall bladder problems, cough, urinary tract infections, skin diseases, diabetic
wounds, and menstrual discomfort [3], [4]. It can be a potent immunostimulator and anticancer drug [11]. Many reports indicate that curcumin can regulate blood sugar levels, decrease blood
pressure, protect nerve cells, and enhance immunity. Therefore, curcumin may be especially
beneficial for the elderly in the prevention and treatment of age-related disorders
like diabetes and diabetic complications as well as neurodegenerative and cardiovascular
diseases [5].
As mentioned above, polyphenol curcumin has antioxidant, anti-inflammatory, anticancer,
antiangiogenic, wound healing, and antimicrobial properties. Due to these properties,
curcumin has been shown to be efficient for the treatment of numerous chronic diseases
including various types of cancers, diabetes, obesity, and cardiovascular, pulmonary,
neurological, infectious, and autoimmune diseases [2], [8], [9], [16]. Furthermore, curcumin can be a synergist to other plant polyphenols with therapeutic
action like resveratrol, catechins, piperine, quercetin, and genistein [2].
Curcuma essential oils, like curcumin, possess a number of biological and medicinal properties,
including anti-inflammatory, anticancer, antiproliferative, hypocholesterolemic, antidiabetic,
antihepatotoxic, antidiarrheal, diuretic, antirheumatic, hypotensive, antioxidant,
antimicrobial, antiviral, insecticidal, larvicidal, antivenomous, carminative, and
antithrombotic effects. These oils can promote functions of the immune system, blood
circulation, detoxication, and digestion (see [3], [4], [16] for reviews).
Curcuma longa extracts possess renal protective, hepatoprotective, cardioprotective, antidiabetic,
neuroprotective, and gonadoprotective effects [2], [4], [6].
Moreover, curcumin can mitigate or prevent the harmful action of environmental contaminants
[15]. For example, it has been shown to reduce genotoxicity, nephrotoxicity, hepatotoxicity,
skin diseases, angiogenesis, reproductive toxicity, neurotoxicity, and immunotoxicity
of arsenic [10]. Either no or no substantial negative curcumin side effects have been observed [4], [16].
Effect on Female Reproductive Processes
Effect on Female Reproductive Processes
Effect on reproductive organs
Feeding rats curcumin did not affect weight of their ovaries or size of their litters
[17]. On the other hand, an artificial pegylated curcumin analogue inhibited rat ovarian
follicle development, sexual maturation, and fecundity [18]. Curcumin promoted ovarian growth, follicullogenesis [19], and mitigated the age-dependent suppression of ovarian functions in mice [20], d-galactose-induced ovarian failure in mice [21] and ovarian failure induced by cyclophosphamide in rats [22]. Dietary curcumin promoted ovarian follicullogenesis and ovulation in the fish Pseudotropheus socolofi
[23]. The plant additive containing curcumin promoted ovarian follicle development in
the buffalo as well [12]. On the contrary, Destici Isgoren et al. [24] did not observe an effect of the curcuma extract on rat ovarian follicle development.
Feeding rabbits turmeric powder did not influence their ovarian size or weight, but
it increased the number and diameter of ovarian follicles. It did not affect rabbit
fecundity but increased the viability of their pups [25].
Tossetta et al. [15] presented evidence that curcumin can be useful for managing pregnancy complications
(preeclampsia, gestational diabetes mellitus, fetal growth retardation, preterm birth,
and response to toxins and pathogens).
Therefore, the data listed above suggest curcumin can both up- and downregulate puberty,
ovarian follicullogenesis, and fecundity, as well as prevent complications during
pregnancy. The character of its effect depends on the animal species and experimental
model.
Effect on ovarian cell functions
One in vitro study showed a suppressive effect of curcumin on basic healthy ovarian cell functions.
In a study by Kádasi et al. [26], the addition of curcumin reduced proliferation and viability and promoted apoptosis
in cultured porcine ovarian granulosa cells. Numerous studies on ovarian cancer cells
showed the ability of curcumin to inhibit the cell cycle and to promote apoptosis
[8], [13], [17], [27], [28], [29], [30], [31], [32], [33], [34], [35].
In vivo studies have shown the opposite, stimulatory action of curcumin and its analogue
on murine ovaries. In these studies, curcumin stimulated proliferation and inhibited
apoptosis in murine [21], [35], [36], [37] and rat [24] ovarian cells. Moreover, curcumin stimulated ovarian oogenesis in mice [19], [36], [37]. Therefore, the available publications demonstrate the curcumin has an influence
on ovarian cell mitosis, meiosis, apoptosis, and viability.
Effect on reproductive hormones
In vivo experiments demonstrated the ability of curcumin to decrease the concentration of
gonadotropins FSH (follicle stimulating hormone) and LH (luteinizing hormone) in rat
serum [19], [22]. Surprisingly, a decrease in gonadotropin release was associated with a rise in
the serum level of estradiol and anti-mullerian hormones [19], [22], which should be upregulated by gonadotropins [38]. Rabbits fed curcumin had an increase in the ovarian production of progesterone
but a decrease the ovarian release of testosterone and leptin. Moreover, feeding rabbits
curcumin altered the response of ovarian cells to LH, as LH reduced leptin release
by ovarian cells of the control rabbits but increased leptin release by ovarian cells
of rabbits fed curcumin [25].
In vitro experiments also showed the stimulatory influence of curcumin on progesterone and
testosterone release by cultured porcine granulosa cells [26], and its inhibitory action on progesterone release by cultured luteal cells from
rat ovaries [39].
Some experiments, however, did not show any curcumin influence on FSH, progesterone,
or estradiol [17] or anti-mullerian hormones [24] in rat plasma. Moreover, they demonstrated a curcumin-induced increase in LH and
a decrease in prolactin concentration in the plasma of rats fed curcumin [17]. Thus, the performed studies demonstrated that curcumin influences (1) the release
of gonadotropins by pituitary cells, (2) the release of hormones by ovarian cells,
and (3) the response of ovarian cells to gonadotropins.
Mechanisms of action on female reproductive processes
It can be easily noted that the curcumin effects observed in in vivo and in vitro studies are different, and sometimes contradictory. This fact indicates the action
of curcumin directly on ovarian cells and on their upstream regulators. The best-known
endocrine and paracrine/autocrine regulators of reproductive and other physiological
actions are hormones. It is well documented that fecundity is defined by the growth,
development, and atresia of follicles in the ovary, and that these processes are under
the control of gonadotropins, ovarian steroids, and peptide hormones [38]. The previous sections of this review have demonstrated that curcumin can influence
pituitary and ovarian hormones, which can mediate curcumin action on reproductive
processes.
Curcumin as a phytoestrogen [40] can interact with the steroid hormones and their receptors, affect the hypothalamo-hypophysial-ovarian
axis, and treat some reproductive disorders [41]. For example, in mouse ovaries, curcumin can suppress androgen receptors and stimulate
3-beta-hydroxysteroid dehydrogenase [20], although it does not affect aromatase [42]. Furthermore, curcumin mitigated the action of dehydroepiandrosterone on mouse ovarian
cell apoptosis [35]. Therefore, the influence of curcumin on ovarian functions and state could be mediated
by its action on ovarian steroid hormone receptors.
There are indications that curcumin action on the ovary (at least the ovary suffering
from polycystic ovarian syndrome) can be mediated by its suppressive action on inflammation
[6] and inflammation-related cytokine interleukin-6, tumor necrosis factor-α, C-reactive protein [43], growth factors GDF-9 and BMP-15 [19], [44], and vascular endothelial growth factor [6].
Furthermore, the influence of curcumin on intracellular regulators of the cell cycle
and apoptosis in healthy [21], [26], [35], [36], [45] and cancer [6], [13], [28], [30], [33], [34] cells suggests that these regulators could be mediators of curcumin action on ovarian
cell functions. Viability, proliferation, and apoptosis of ovarian cells should affect
their hormone release as mentioned above, although the opposite effect of steroid
and peptide hormones on ovarian cell proliferation and apoptosis has also been documented
[35], [38].
Curcumin action on ovarian cell mitosis and apoptosis can be mediated by its action
on transcription factor p53, which stops the cell cycle, promotes DNA reparation,
and induces apoptosis in defect or cancer ovarian cells [6]. On the other hand, there is evidence that p53 does not mediate the stimulatory
action of curcumin on apoptosis in ovarian carcinoma cells. Evidence has shown that
curcumin can activate proliferation promoter p38 mitogen-activated protein kinase
(MAPK) and downregulate antiapoptotic peptides Bcl-2 and survivin and Akt signaling
[28]. The involvement of MAPK in mediating curcumin action has also been demonstrated
for healthy ovarian cells [39].
The results of other studies have indicated that curcumin action on ovarian cancer
cells or ovarian cells suffered from polycystic ovarian syndrome could be mediated
by transcription factor STAT, matrix metalloproteinase-9 [6], sarco/endoplasmic reticulum Ca2+ ATPase [30], 5′ AMNe-activated protein kinase, NF-κB, heat shock protein 70 [33], [36], PI3K/Akt and Nrf2/HO-1 [21], AKT/mTOR/p70S6K [13], Wnt/β-catenin signaling pathways [33], and enzymes SIRT-1 and SIRT-3 [44].
The antioxidant curcumin can bind reactive oxygen species and, therefore, prevent
peroxidation and degradation of nucleic acids, peptides, lipids, and the consequent
apoptosis, aging or malignant transformation of healthy cells, but not cancer cells
[6], [19], [44]. It is not to be excluded that the protective effect of curcumin against pregnancy
complications could also be due to its antioxidant properties [15]. Recently, the involvement of some microRNAs and long non-coding RNAs in regulating
various types of cancer cells and curcumin action on these cells have been indicated
[13], [33].
Application in Reproductive Biology and Medicine
Application in Reproductive Biology and Medicine
The available reports regarding curcuminʼs effect on reproductive processes allows
for outlining possible areas of its application. The ability of curcumin to promote
ovarian follicullogenesis and fecundity in laboratory rodents [18], [19], [21], [35], [36], [37] and rabbits [25]
in vivo indicates its potential applicability as a natural biostimulator of reproduction
in large farm animal production. Furthermore, its ability to improve oocyte maturation,
quality, and developmental capacity [19], [36], [37], [45] suggests that its addition could be beneficial for in vitro oocyte maturation, fertilization, and embryo production.
Furthermore, evidence suggests its applicability for the prevention, mitigation, and
maybe even treatment of some age-dependent reproductive disorders including late sexual
maturation [19], [20], reproductive aging, ovarian insufficiency and failure [5], [20], [21], [22], [24], [36], [37], complications during pregnancy [15], and a prolonged postpartum period [12]. Moreover, its potential to prevent, mitigate, and treat signs of ovarian cancer
[8], [11], [13], [17], [27], [28], [29], [30], [31], [32], [33], [34], polycystic ovarian syndrome [35], [43], [44], and adverse effects of immunological shock [36], hypoxia [46], ionizing irradiation [45], ischemia [47], oxidative stress [44], [48], mykotoxins [48], and arsenic [10] on ovarian functions suggests the large therapeutic potential of curcumin and its
molecules.
It is, however, necessary to note that wider application of curcumin can be limited
by its relatively low solubility, bioavailability, bioabsorption [1], [29], [49], and stability in light and in organisms [34]. To improve these physicochemical and therapeutic characteristics, the following
approaches have been tested:
-
Synthetic curcumin analogues with enhanced bioabsorption and a higher ability to block
reactive oxygen species and cancer development [29].
-
Application of curcumin nanoparticles with higher absorption, transport through cell
membranes and accumulation in the ovary [49], with increased stability and a proapoptotic effect on cancer cells [34], or with enhanced antiparasitic properties [16].
-
A combination of chemical modifications of curcumin and the generation of nanoparticles
from the modified curcumin [32].
-
The application of lipid [9], [16], [31] or metal [35] nanoparticles as carriers for curcumin transport.
The chemical modifications of curcumin and its carriers could expand the possibilities
and efficiency of its application in animal production, biotechnology, and human and
veterinary medicine.
Conclusion and Possible Directions of Further Studies
Conclusion and Possible Directions of Further Studies
Rhizomes of Curcumas contain various biologically active substances, the best-known of which is polyphenol
curcumin, which has a wide array of biological and medical effects. Its influence
on female reproduction (puberty, reproductive aging, ovarian follicullogenesis and
oogenesis, and fecundity) has been well documented. Curcumin can affect these processes
via changes in the release and reception of pituitary and ovarian hormones, growth
factors and cytokines. Furthermore, it can influence the response of ovarian cells
to these substances and external environmental factors. Finally, curcumin can affect
oxidative processes within the ovary and numerous intracellular signalling pathways
related to ovarian cell proliferation and apoptosis. These effects described in the
details above suggest the applicability of curcumin for stimulation of female reproductive
processes in vivo and in vitro, as well as for the prevention, mitigation, and treatment of
various reproductive disorders from ovarian insufficiency and infertility to polycystic
ovarian syndrome and ovarian cancer.
On the other hand, numerous aspects of Curcumasʼ influence and application in the control of female reproduction require further studies.
Previous investigations were focused mainly on curcumin, whilst reproductive effects
of other constituents of Curcumas, including curcumin derivatives and curcuma oils, remain not studied as of yet. Hierarchical
interrelationships between numerous mechanisms of curcumin action on reproduction
require further elucidation. It could help to understand the causes of different actions
of curcumin in vivo and in vitro on healthy cells and cancer cells. The available information concerning the effect
and potential applicability of curcumin listed above was obtained mainly during animal
and in vitro experiments, while clinical studies remain rare and insufficient. Increased bioavailability
and efficiency of curcumin requires further efforts of specialists in chemistry and
medicine. Nevertheless, the available
information demonstrates that curcumin can be a promising, inexpensive, accessible,
and efficient natural regulator, protector, and medicine for animal and human female
reproductive processes.
Contributorsʼ Statement
The manuscript has been generated by one author.
