1 Introduction

Cervical cancer (CC) is one of the most common gynecological cancers among women globally, the current rate of CC worldwide is calculated at approximately 660.000 new cases in 2022/23 with 350.000 deaths mainly occurring in low- and middle-income countries such as sub-Saharan Africa (SSA), Central America and South-East Asia [1, 2]. Numerous studies have defined the plethora of CC and BC clinical symptoms allowing to describe a specific psychological and psychiatric profile [1, 2]. According to recent data, the prevalence of anxiety and depression is high among women with breast cancer (BC) and CC, harming the quality of life [3,4,5,6]. The variegate spectrum of depression and anxiety disorders, which includes panic disorder (PD) and agoraphobia, obsessive–compulsive disorder (OCD), phobic disorder, and post-traumatic stress disorder (PTSD) among peri- and post-menopausal women has been estimated at approximately 41.8%. Of all women, 23.2% were premenopausal and 56.9% were postmenopausal. Selective serotonin reuptake inhibitors (SSRIs) are the antidepressant drugs most commonly prescribed to women (71.0%) affected by these conditions, particularly in the 45 to 65 age group. With the discovery of new psychotropic medications, specific diagnosis within this spectrum is essential because each of these disorders responds to specific pharmacotherapy. The approach to anxiety and depression should also recognize are often comorbid conditions (χ2 P < 0.05) [7, 8].

Many are the studies focusing on the peri and post-menopausal vasomotor symptoms but fewer on peri and post-menopausal depression [5, 6]. Peri- and post-menopause are accompanied by important physiological and psychological changes, in which depression and anxiety are probably the most important features. Menopause itself does not cause cancer, but during this period the risk of developing cancer increases with a higher incidence among women aged 60–65 years and older [9, 10]. There is an age-mediated inflamed microenvironment, which enhances autoimmune and inflammatory responses with decreased protective immune capacities. The peri- and post-menopause period is widely recognized as a period characterized by a higher proliferation rate of harmful microorganisms in the vaginal microenvironment [11,12,13]. Studies conducted on middle-aged women have shown a strong correlation between hormones, eating disorders, intestinal and vaginal dysbiosis, sleep disorders, anxiety, depression, and inflammatory patterns. Improvements in dysbiosis following a low-glycemic index diet, and better sleep quality were seen as favorably associated with improved inflammation levels with positive effects on depression and anxiety [11,12,13,14,15,16]. Ever since, the main therapeutic answer was the use of antidepressant medication considered crucial in containing the intensity of symptoms, since these drugs have even been found useful in inflammatory processes, at least in the short term [17,18,19,20,21,22]. Overall outcomes confirmed that the median age at the time of the index Pap test and human papillomavirus (HPV) test was 37 years (range 30–59 years) in the premenopausal cohort and 60 years (range 42–74 years) in the postmenopausal cohort [19,20,21,22,23]. HPV prevalence was 22.6% among all women, 41.6% among premenopausal women, and 11.5% among postmenopausal women. Of note, the results confirmed the presence of invasive tumors with a ratio four times higher in the perimenopausal group and two times higher in the postmenopausal group, as to say the higher the dysbiosis, the higher the presence of harmful microorganisms and the higher the chances of developing malignancies [23,24,25,26].

Although no one can deny the therapeutic validity of antidepressants, especially SSRIs, some considerations must be made, especially concerning their effectiveness in long-term therapy. The consumption of antidepressants (mainly SSRIs) at clinically relevant concentrations would play a role in tissue mutation and CC onset in adult women during the peri-post-menopausal periods [27,28,29,30]. Here we focused on two interrelated aspects; (i), the dysbiosis-immunity-carcinogenesis axis following exposure to antidepressant drugs, and (ii) the possible role of antidepressants in promoting the antibiotic resistance mechanism of oncogenic pathogens; in this regard, a particular attention was given to HPV, E. coli, P. aeruginosa, Staph. aureus, and Streptococcus agalactiae. Outcomes from three of the most common antidepressant drugs belonging to the SSRI class such as sertraline, duloxetine, and fluoxetine have confirmed a profound influence on bacterial resistance to antibiotics even at very low doses, due to the increase in bacterial oxidative stress (OS) and ROS [27,28,29,30,31,32,33,34, 34, 35, 35, 36, 36, 37, 37, 38, 38,39,40] (Fig. 1).

Fig. 1
figure 1

An outline map of the hypotheses to explain depressive disorders and possible contribution effects of antidepressant. (I) Aging that involves biological and structural changes including HPA axis dysfunction in which hormones are either high or low levels such as cortisol, thyroid hormone (TH), testosterone, progesterone and estrogen etc…; (II) the neuro-immune-endocrine hypothesis which indicate the functional deficiency of serotonin (5-HT), dopamine and norepinephrine, and the neuro-inflammation induced by reactive oxygen species (ROS), inflammatory cytokines and inflammasomes activation (TLRs, IL-6, IL-1b, TNFa is suggested to promote the occurrence of MDD; (III) the structural and functional remodeling hypothesis of SSRIs which suggests that patients with long-term treatment with SSRIs promote further structural changes that support the onset of CC

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To fill these gaps, we attempted to generate a logarithm based on a logistic growth model. We conducted a large-scale study highlighting the main traits that may connect the CC onset to dysbiosis, immunity decay, and microorganisms, including the role of hormones, menopause, and lifestyle as important risk co-factors [41, 42].

2 Types of antidepressants

There are different types of antidepressants based on their mode of action, goals, and chemical structure [41]. The effects of antidepressants are based on how they affect certain brain pathways and neurotransmitters, such as serotonin, dopamine, and norepinephrine, which are responsible for transmitting signals from one nerve cell to another in the brain [41,42,43]. The basic theory is to maintain available levels of neurotransmitters, which tend to improve communication between nerve cells, strengthening brain circuits and therefore also acting on mood [41,42,43].

2.1 Selective serotonin reuptake inhibitors (SSRIs)

SSRIs are currently the most widely prescribed type of antidepressant mainly due to lower side effects. Fluoxetine or Prozac, is probably the best known. Other SSRIs include citalopram (Cipramil), escitalopram (Cipralex), paroxetine (Seroxat), and sertraline (Lustral). Normally neurotransmitters are reabsorbed back into nerve cells in the brain after they are released to send messages between nerve cells, this class of inhibitors prevents neurotransmitters from getting reabsorbed, to remain at least temporarily in the synapse [40,41,42,43].

2.2 Serotonin-noradrenaline reuptake inhibitors (SNRIs)

SNRIs similar to SSRIs and originally designed to be more effective than SSRIs in clinical settings have since shown less robust results. SNRIs include duloxetine (Cymbalta and Yentreve) and venlafaxine (Effexor). The SNRIs work by inhibiting the uptake of serotonin and norepinephrine through the presynaptic neuronal uptake mechanism following release from the synaptic cleft [44,45,46,47]. The idea is to prevent reuptake that prolongs the persistence of these monoamines in the synaptic cleft within the central nervous system (CNS), which could eventually result in increased postsynaptic receptor stimulation and prolonged postsynaptic neuronal transmission [44,45,46,47]. Furthermore, data have shown that increasing norepinephrine levels while maintaining serotonin levels may be particularly useful in treating patients with psychomotor retardation [44,45,46,47].

3 Depression and anxiety patterns of an inflammatory disease the role of SSRIs; the good side and bad side

With an increase of approximately 18–20% in the last decade, depression and anxiety are estimated to be the second leading causes of disability globally by 2020 and 2030 [48]. According to the recent World Health Organization (WHO), depression is a major global health problem with 3.8% of the population, of which 5–6% are adults older than 60 years [48]. Since the 1980s there has been strong interest in evaluating the relationship between depression and the immune system as it has been noted that inflammatory diseases, for example, rheumatoid arthritis and fibromyalgia, are accompanied by depression [47,48,49,50]. Finding confirmed the presence of abnormal cytokines and interleukins in depression that can modulate brain neurotransmission by bidirectionally influencing the hypothalamic–pituitary–adrenal/gonadal (HPA-G) axis and intestinal/vaginal microbiota [51,52,53].

Typical depressive patterns were observed in in vivo studies in which healthy participants were given endotoxin infusions to trigger cytokine release, something similar seen in many patients who received interferon to treat hepatitis C [53,54,55]. Exacerbated inflammatory responses have often been observed following acute psychological and physical stress, and emotional or traumatic incidents resulting in increases in interleukin 6 (IL-6), C-reactive protein (CRP), interferon-gamma (IFN-γ), and alpha tumor necrosis. TNF-α) following the activation of nuclear factor kappa B (NF-kB), a natural indicator of an ongoing inflammatory process [53,54,55]. An increase in circulating levels of other proinflammatory cytokines such as interleukin 1 beta (IL-1β) has also been reported in depressed patients [53,54,55].

While depression and anxiety seem to produce an increase in inflammatory markers in some patients, in patients under SRRIs treatment a decrease in the inflammatory process has been observed, including a reduction of natural killer (NKs) and dendritic cells (DCs) level [55,56,57,58]. However, long-term use of some antidepressants has been shown to have a proinflammatory action associated with higher levels of CRP and IL-6 and substantially related to weight gain, the presence of metabolic syndrome, hormonal imbalance, and dysbiosis due to greater consumption of foods with a high glycemic load (GL) [59,60,61,62]. The neuroendocrine theory has focused on the pathophysiological mechanism that afflicts the homeostasis of the hypothalamic–pituitary–adrenal (HPA) axis, which responds with a hyperactivation of the stress response. Researchers have demonstrated how hormones such as serotonin, cortisol, leptin, and ghrelin may fluctuate in individuals suffering from depression and anxiety as a consequence of antidepressant treatment, due to a reduced response of the HPA axis. Long-term use, generally longer than a year can cause downregulation of serotonin receptors, which subsequently causes cravings for carbohydrate-rich foods such as bread, pasta, and sweets that ultimately may lead to weight gain [59,60,61,62].

Furthermore, the adipose tissue hormone leptin, outcomes confirmed its potential role in depression and anxiety. Treatment with amitriptyline or mirtazapine increased plasma leptin concentrations only if administered shortly, while plasma leptin levels remained unchanged with treatments with paroxetine and venlafaxine. Something that was later confirmed by results obtained with intrahippocampal, but not intrahypothalamic, administration of leptin that led to an antidepressant-like action in rodents, suggesting that leptin-induced antidepressant actions were not secondary to the metabolic effects induced by leptin [63].

3.1 The role of antidepressant in pathogen resistance

Both ex vivo and in vitro results of long-term antidepressants in chronic depression have demonstrated a resumption of the inflammatory process following the activation of T cells accompanied by a sort of "resistance" of the immunosuppressive response. The long-term use of antidepressants also seems to lead to a breakdown of the immune response due to the increase in oxidative and nitrosative stress, and the onset of autoimmune reactions [63,64,65,66]. Interestingly, data from a recent study showed how the conjugation mechanism occurs together with ROS scavengers under anaerobic conditions flow cytometric analysis detected a rise in the production of ROS with an increase in cell membrane permeability [66,67,68]. Genomic analysis, quantitative proteomics, and RNA sequencing helped highlight the whole genome with total mutations of the bacteria, results considered together with the de-repression of conjugation-relevant genes following exposure to antidepressant drugs. For example, increased levels of ROS have been observed in E. coli, due to long-term intake of fluoxetine, in combination with a series of mutations subsequently involved in resistance to different classes of antibiotics such as fluoroquinolones, aminoglycosides, β-lactams, tetracyclines and chloramphenicol [65,66,67,68].

Of note, the upregulated genes at the transcriptional expression level were all responsible for antioxidant defense with strong protective activity against ROS damage. In E. coli, exposure to sertraline, duloxetine, and fluoxetine activated sets of genes including those encoding alkyl hydroperoxide reductase (ahpC, ahpF), hydroperoxidase I (katG), and superoxide dismutase (sodA, sodC). The outcomes showed the antidepressant's ability to promote the conjugal transfer of bla NDM − 1 positive plasmid from uropathogenic E. Coli to local bacteria P. alloputida. Plasmids are prevalent antibiotic-resistant gene carriers (ARGs-carriers) among E. coli, and 81% of uropathogenic E. coliisolates were plasmid-positive [63].

The underlying mechanisms revealed that antidepressants tend to affect the SOS responses and plasmid conjugative transfer as well. The SOS pathway is a well-known DNA damage repair system and a central motive in bacterial adaptation, pathogenesis, and diversification. Furthermore, these events were seen as dose-dependent, the higher the dose of antidepressant drug (sertraline, duloxetine, fluoxetine, bupropion, and escitalopram) the higher the mutations. Sertraline, duloxetine, and fluoxetine exhibited the strongest impact in promoting the conjugation mechanism (p adj < 0.01). The authors observed the conjugation even at lower concentrations (1.0 mg/L) of sertraline (p adj < 0.01) and duloxetine (p adj < 0.05) [63,64,65,66].

The abundance of proteins associated with DNA repair genes confirmed that antidepressants are capable of triggering the SOS response [63, 67,68,69]. In particular, sertraline, duloxetine, fluoxetine, and bupropion were shown to trigger the SOS response with higher impact. In vitro, the donor bacterium showed a pair of up-regulated genes relevant to the SOS response such as the lexA and recA, constituent parts of an error-prone repair system that contributes significantly to DNA changes, that are also involved in the ROS responses. Therefore, over-expression of LexA and RecA not only can be considered indicators for DNA damage but are proportional to DNA damage [63, 67,68,69]. The authors observed sertraline and duloxetine capable of upregulating the transcription of uvrB also involved in the recognition of DNA damage and repair. In the recipient strain, genes that respond to DNA damage were also upregulated, including genes encoding DNA mismatch repair proteins (mutL, mutS), the gene encoding a DNA repair enzyme (radA), genes relevant to the SOS response (recC, recF, recQ, recR), and the cell division inhibitor gene (sulA) [67,68,69].

4 The gut/vagina microbiome

Recent findings have highlighted the fundamental role of microbiome in human health and immune systems performances. Microbiota, tend to change with age, especially under the weight of food, antibiotics use, antidepressants, and diseases [15]. With age and dysbiosis the balance of many immune cells such as NKs, macrophages, and DCs start losing their tolerance which is proven by low expression of costimulatory molecules, an increase in proinflammatory cytokines, deterioration in phagocytic activity, and the inability to induce Tregs, leading to increased chances of autoimmune and inflammatory disorders [15, 70,71,72,73]. While the main reason behind the tolerance is the enhanced proinflammatory responses and activation of NF-κB, the increase in antibiotic resistance of some bacteria following antidepressant drugs occurs in a dysbiotic microenvironment, the bacteria of an intestinal or vaginal district can transfer this property to bacteria residing in different districts, such as the mouth or the respiratory tract [15, 70,71,72,73]. Data tends to highlight that different selective pressures in the urinary tract allow E.coli, K. pneumoniae, and different other local strains to preserve their motile capability exploiting local population heterogeneity, which might be seen as a tool to prevent host recognition and bacterial killing [63,64,65,66,67]. Of note, the pharmacodynamics of these drugs revealed something interesting, as most antidepressants are excreted through the gastrointestinal (GI) tract and kidneys in feces and urine (Figs. 1, 2) [63,64,65,66,67].

Fig. 2
figure 2

SSRIs and SNRIs and associated collateral effects on intestinal and vaginal microbiota. Here we described the SSRIs role and hallmarks in driving systemic inflammation in favoring dysbiosis and microorganism infection, especially oncogene viruses and bacteria such as HPV, C. trachomatis, P. aeruginosa, E. coli etc…. Numerous are the co-causative factors, including gut and vagina aging, low hormones, cigarette, dietary habits, and sedentary lifestyles, that contribute to a spectrum of immunological phenomena (Gargiulo)

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At different concentrations, once absorbed, antidepressants freely circulating with a half-life between 1–2 h (agomelatine) and 14 h (fluoxetine), favoring continuous contact with local and commensal opportunistic microorganisms of the intestine and urinary tract, such as the C. trachomatis, Strep. agalactiae, P. aeruginosa and E. coli [1, 63,64,65,66,67]. Therefore, antidepressants in the urine and urogenital tract could contribute to the exchange of plasmids between different types of bacteria resulting in the emergence or evolution of dangerous multi-antibiotic-resistant superbugs and complicated infections that are difficult to eradicate [68,69,70]. A significant association was found between antidepressant drugs and urinary tract infection (UTI) in men aged 45–69 years (n = 63,579; OR = 1.36, 95% CI 1.29–1.44) which consolidates the possible negative impact on urinary microbiome with a consequent dissemination of antibiotic resistance [70].

Like the intestinal microbiota, the vaginal microbiota also plays important physiological functions for human psycho-cognitive and emotional processes, mainly thanks to its role in the metabolism and synthesis of numerous hormones, neurotransmitters, and neuropeptides [1, 7]. Therefore, to see the involvement of antidepressant drugs in the onset of CC, we must highlight the role of vaginal and/or intestinal microbiota as an important player in immunity both as immune modulators and pathogen surveillance. As previously highlighted, an unbalanced diversity of bacterial strains is directly involved in the risk of highly inflammatory processes and metabolic diseases [1, 7].

Despite the importance of the vaginal microbiota, surprisingly little is known about how it protects the female reproductive tract or any other role it plays as a regulator of the vaginal ecosystem. Just like pure commensal microorganisms, the so-called “bad bacteria” are also part of the human flora ecosystem [71,72,73,74]. However, under favorable conditions, microorganisms such as streptococcus can transform from commensals into opportunists, favoring even serious infections in the host [71,72,73,74].

Indeed, projections indicate that up to approximately 30% of new cases of CC could be the consequence of a chronic alteration of the vaginal microbiota. A decomposition of local Lactobacillus spp. in the vaginal microbiota can lead to clinical dysfunctions, such as bacterial vaginosis (BV), a recurrent, symptomatic, and polymicrobial event that represents the most common vaginal disorder in women during reproductive age [75,76,77,78]. These diseases and adverse outcomes include the acquisition of infections transmitted by viruses such as HPV and human immunodeficiency virus (HIV), or bacteria such as C. trachomatis, E. Coli, P. aeruginosa, Streptococcus agalactiae, and U. parvum, all considered important causes of preterm birth, miscarriage, chronic pelvic inflammatory disease, and CC [1, 75,76,77,78,79,80].

4.1 A common origin and evolution pathway across the millennia of commensal pathogens, microbiota, and human cells

There is a paradigm shift in our understanding of microorganisms in general, which has led to considering eukaryotic cells as meta-organisms, an inseparable part of the microbiota as its own functional machine [80, 81]. Therefore, given the intimate interaction between microbiota, commensal and non-commensal microorganisms, and the host immune system, many scientists have agreed on the common origin and coevolutionary progress of bacteria, viruses, and host cells during which they exchanged some important traits functionally mediated by different forms of genetic recombination [81, 82]. The evolutionary process of modern viruses, bacteria, and even tumor cells is essentially based on maintaining the capacity for mutation (substitutions, additions, deletions), recombination, or reassortment to better adapt and evolve against external and internal adversities [80,81,82].

The human microbiome, found almost everywhere in the body, has helped improve defense against pathogens, metabolic health, and regulation of the immune system. During the long process of coevolution, the most important challenge faced by the host immune system was to improve its ability to distinguish between beneficial and pathogenic microbes [83, 84]. On the other hand, the commensal microbiota is capable of influencing many aspects of the T cell differentiation process, thus improving the continuous changes necessary to the host genome contributing to the full efficiency of the adaptive immune system [83, 84].

Sharing similar molecular patterns, the innate and adaptive immune systems have achieved a very high degree of discrimination capacity in distinguishing between microbes and microorganisms by recognizing specific molecular sequences and triggering both pro- and anti-inflammatory responses depending on the nature of the antigen. In particular, CD4+ and CD8+ T cells, thanks to their versatility and plasticity with their numerous subsets, have developed the ability to interface with the human microbiota [83,84,85,86].

The microbiota varies in different anatomical parts in the gut proteobacteria such as Enterobacteriaceae are found in the small intestine but not the colon, while Bacteriodetes such as Bacteroidaceae, Prevotellaceae, Rikenellaceae are often found in the colon. The vagina is mainly composed of Lactobacillus, Prevotella, Gardnerella, C albicans, Atopopium, Dialister, and Sneathia; the cervix is composed of Lactobacillus, Prevotella, Gardnerella, and Veilonella; the endometrium is composed by Lactobacillus, Prevotella, Streptococcus, Bifidobacterium, and Flavobacterium; in the ovaries we may find Lactobacillus, Prevotella, Actynomices and Staphylococcus; in the uterine tubes Lactobacillus, Prevotella, Enterococcus, Pseudomonads, Proprionibacterium and Staphylococcus [87,88,89,90].

4.2 Microbiota of the female genital tract and possible crosstalk with different systems

Though the gut microbiota has been studied extensively, little is known about the complexity and dynamic nature of the cervicovaginal microbiota, especially about female immunity and CNS psychological outcomes [91,92,93,94,95]. In general, each single tract of both gut and vaginal microenvironment is homed by a multitude of different microorganisms with different tasks and targets. Specifically, the female intestinal and genital microenvironment has a microbiota that varies due to age and external factors (e.g. diet and drugs). Furthermore, pathogens represent only a small portion of the total number of microorganisms; dysbiosis, which describes the altered composition of the microbial flora, indicates the migration and homing of bacterial strains from an original district to other locations [82]. The intestinal and cervicovaginal microbiota are correlated with other organs and systems having shown a great influence on the general health of the host by interfacing directly and indirectly with the neuro-endocrine-immune systems [91,92,93,94,95].

The two microenvironments are closely related through a complex network of microorganisms homed there. Scientists have defined this dense communication network as highly active crosstalk. Interestingly, the origin of many of the microorganisms that colonize the cervicovaginal space has been traced back to the rectum, which also acts as a reservoir [96,97,98,99,100]. Results obtained from a cohort study of 132 pregnant women showed that 36% of the species, of which 68% share identical genotypes (rectum and vagina), share almost 50% of the good flora, including cell density for bacterial species [91,92,93,94,95,96].

The effective interface between vaginal microbiota and other districts derives from studies that have demonstrated the mobility of bacteria from one site to another, e.g. between the oral cavity and the vagina. Periodontitis is often associated with an increased risk of preeclampsia, intrauterine growth retardation, premature birth, and delivery of low birth-weight infants [96,97,98,99,100].

Of note, Porphyromonas gingivalis, Prevotella intermedia, and Porphyromonas endodontalis are the typical oral flora found in the amniotic fluid of women in preterm labor [96,97,98,99,100,101]. Similarly, the strain of Bergeyella spp. absent in the vagina of a pregnant woman with clinical chorioamnionitis was identified in both amniotic fluid and subgingival plaque. Fusobacterium nucleatum, a typical commensal oral anaerobe, has also been found in various locations of the female urogenital tract, in the placenta where it favors the colonization of other pathogens such as E coli or is seen as a co-cause of endometriosis [96,97,98,99,100,101]. Changes in the composition of the microflora and local bacteria or dysbiosis can be generated by different conditions, of which the most common can be attributed to the different levels of sexual hormones such as estrogen, progesterone DHEA and glycogen that are observed during the menstrual cycle, during pregnancy or peri-post menopause [100, 101].

It should be remembered that peri-post menopause, hormonal decline, metabolic disorders, inflammation, mood changes, the onset of depressive and anxious states are all events that tend to develop over a long period of time, decades in a crescendo manner; the use of antidepressant drugs probably becomes the doctor's main therapy in an attempt to restore balance, reduce inflammatory processes and rebalance mood in affected patients [82, 91,92,93]. However, it should be noted that this type of symptomatology is linked to the healthy composition of the vaginal microbiome which determines the responses of the local immune system also towards non-dangerous but nevertheless off-site microorganisms. However, once dysbiosis is established, tolerance to these microorganisms often gives rise to progressive silent infections with the tendency to manifest even after decades, inducing mutations that eventually lead to carcinogenesis [102,103,104,105,106].

5 Serotonin and steroid hormones the neuro-endocrine-gut/vagina cross-talk: organizational effects

The composition of the vaginal microbiota and its multiple functions are profoundly correlated with two classes of hormones, (i) steroid hormones such as DHEA, testosterone, estrogen, and progesterone, (ii) serotonin also known as 5-hydroxytryptamine (5-HT), a monoamine neurotransmitter. The role of the vaginal microbiome in the balance of immune and hormonal homeostasis has also proven effective in the surveillance of bacterial virulence genes, acting through the bacterial sensor histidine kinase CpxA (Table 1) [52, 75, 106,107,108,109,110,111,112].

While much of the production of serotonin in the human body occurs in the intestine, primarily due to intestinal enterochromaffin cells, serotonin influences female sexual functioning through peripheral mechanisms [5]. Serotonin is the main neurotransmitter used by enteric neurons in the regulation of intestinal motility and, interestingly, there is also evidence of serotonin production and turnover by the vaginal microbiome itself [52, 53].

Interestingly, the vaginal microbial community can be influenced by a mechanism mediated by the estrobolome (collection of microorganisms) that can metabolize estrogens such as Bifidobacterium, Clostridium, and Lactobacillus involved in both hepatic deconjugation and estrogen conjugation in the GI tract. Consequently, the amount of estrogen-metabolizing bacteria within the gut microbiota may also influence the amount of Lactobacillus in the vaginal microbiota. Furthermore, the crucial role of estrogens in making serotonin available, by inhibiting the degradation of serotonin through the activation of monoamine oxidase (MO) and the reuptake of serotonin from the synaptic cleft to the presynaptic neuron, is also a widely confirmed mechanism [113,114,115,116,117,118,119,120,121]. Estrogen, progesterone, and DHEA have shown a positive effect on both the innate and adaptive immune systems promoting more effective protection of the female reproductive tract from invading pathogens [122,123,124].

6 Influence of SSRIs on the serotonin/estrogen axis and systemic effects

While SSRIs have been shown to have overall higher tolerability and safety than older antidepressants (tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), long-term intake has shown some issues. Any antidepressant tends to lose its effect after a long period, mainly due to drug tolerance. The adopted solutions generally include a higher dose or change to a different antidepressant with a different mechanism of action [41, 125, 126]. In any case, the effects of long-term administration have not been sufficiently taken into consideration. The 6 to 8-week duration of general clinical studies may be insufficient to describe adverse events that only become evident with a longer treatment period, especially considering the positive effects of short-term use. For example, SSRI-induced hyponatremia may go undetected in short clinical trials due to the time required for detection and its symptoms, which are generally nonspecific and could range from confusion, weakness, and lethargy to drowsiness and dry mouth that could also be typical of heart failure [41, 125, 126].

Serotonin in its 5-HT form as a neurotransmitter plays a fundamental role in the development and functioning of the CNS and 95% of the body's serotonin is produced in the intestine where it acts by performing hormonal, autocrine, paracrine, and endocrine activities [127,128,129,130]. Interestingly, duloxetine, fluoxetine, and sertraline, after exerting an initial mood-enhancing effect along with beneficial anti-inflammatory activities, can lead to major metabolic and neurological changes with long-term use [131]. Suffice it to say, inflammatory signs linked to both metabolic and neurological changes have been identified in the placentas of adult children of mothers who encountered an immune challenge during pregnancy [132, 133]. As an important regulator of the body's mood and immune response, babies tend to only receive serotonin from the mother through the placenta during the early stages of pregnancy, so any serotonin deficiency would eventually affect the baby. These markers could be used to help identify specific targets to help mitigate the neurodevelopmental consequences of prenatal environmental stressors, such as an immune response due to stress induction [132, 133].

Serotonin concentration tends to be stable during non-pathological aging, however, low or even stop of serotonin production occurs due to several factors including genetics, the aging process, physical and mental stress, chronic pain, and nutritional deficiencies [75, 106,107,108,109,110,111]. CC is diagnosed most frequently in women in peri-post-menopause with an average age at diagnosis of 50–60 years, often associated with chronic metabolic disorders, chronic vaginal and gut dysbiosis, and often diagnosed with depressive condition. In addition, women with invasive CC, Lactobacillus spp. deficiency and lower vaginal pH are often evident features of the long-term establishment of known pro-cancerous pathogens such as HPV and C. trachomatis [75, 106,107,108,109,110,111].

Although it is known that the damage caused by SSRIs can be long-lasting and there are indications that it may even be permanent, e.g. for sexual and withdrawal disorders, not too much attention seems to have been paid to the damages that can occur at the level of the immune defenses and the microbiota. At this point it becomes necessary to answer two questions; (i), Where can SSRIs re-uptake serotonin once this is no longer available in the body, even considering the SSRI’s involvement in estradiol and serotonin depletion? (ii), But even more, which tissues and cells can be damaged in response to the lack of serotonin? [45].

Data obtained on over 200,000 people and performed over 10 years tends to confirm the insurgence of cardiovascular complications due to long-term use of SSRIs, the most important of which are arrhythmias and syncope probably due to their effect on estradiol level [134]. The results may probably be explained by the SSRIs’ affection for estradiol/serotonin crosstalk systemically. Estrogens were shown to exert a high positive effect on lipoprotein levels, lowering LDL and increasing HDL which is estimated to contribute approximately 30% of cardiovascular benefit in premenopausal women. The long-term use of SSRIs was seen affecting the QT interval prolongation, though rarely leading to life-threatening arrhythmias in therapeutic doses. The Citalopram was seen to have the highest cardiotoxic capacity in a dose-dependent fashion, conduction disturbances, and arrhythmias have been reported together with other types of unwanted effects which included sinus bradycardia and tachycardia, left and right bundle branch block, supraventricular tachycardia, and ventricular fibrillation [134]. Several lines of evidence showed an increased number of both dead and damaged cells upon exposure to medium concentration (10.0 mg/L) of duloxetine, fluoxetine, and sertraline, while it was observed the bactericidal effect of these antidepressants at high concentrations (50.0 and 100.0 mg/L) as no viable colonies were seen growing on the selective plates [63, 68, 69]. On the other hand, bupropion and escitalopram significantly (p adj < 0.01) stimulated conjugation at a broad concentration enhancing the transfer ratio of plasmid RP4 [63, 68].

Thus, we have proposed a series of modifiable and non-modifiable risk factors for the development of CC, characterized by bidirectional patterns since the potential endocrine-immune-microbiota disrupting effects of long-term use of SSRIs on the reproductive system of women may eventually have a role in the pathogenesis of CC [6, 45]. In this regard one of the strongest limitations of previous studies conducted on this matter has been not considering depression as an inflammatory-based condition, a piece of the bigger picture, in which immunity, hormones, metabolic disorders, and CC are all intimately related. If it is true that antidepressant drugs are administered to treat depression, they have also had extensive use in the treatment of some inflammatory conditions and neuropathies of various kinds [37]. We therefore considered the current use of SSRIs somewhat misleading, as the results appear to be inconsistent between studies and the real effects of the drug, especially when considering long-term administration [135,136,137].

6.1 Long-term use of SSRIs, chronic inflammation, and the occurrence of pro-oncogenic pathway, the role and influence of Interleukins and Toll-like receptors

Recent outcome showed how a prolonged use of SSRIs can alter the defense responses of the vaginal and intestinal microenvironment, favoring the growth of microorganisms such as C trachomatis and E coli potentially resistant to antibiotics. These microorganisms contribute to inflammatory processes which, becoming chronic over time, destroy the local epithelial barrier, causing genotoxicity and facilitating a microenvironment permissive to tumorigenesis [63, 68]. Interestingly, both C trachomatis and E coli have shown the ability to induce the epithelial-to-mesenchymal transition of infected cells, inducing loss of epithelial cell adhesion and downregulation that drive DNA-altering events [34, 138, 139].

Of note, cervical carcinogenesis can occur even when cell proliferation is reduced and the multiple effects of antidepressants do not always coincide with increases in the number of tissue changes. Evidences have suggested that the therapeutic actions of antidepressants during the peri-post menopausal period may be related to the remodeling of specific immune cell lineages, such as in DCs, macrophages and neuronal cells, rather than the number per se. This CC growth hypothesis can therefore best be described as the tumor cell neuro-immune-endocrine plasticity hypothesis, an expansion of the concept that would include the cell's differentiation process involving intrinsic inflammatory patterns such as toll-like receptors (TLRs), and mitochondrial activity in response to multiple disturbance mechanisms (Fig. 2) [138,139,140].

TLRs play a crucial role since are widely expressed within the female reproductive system. TLR pathogens stimulation induces immune activation and local expression of inflammatory mediators, they are also involved with cancer angiogenesis, metastasis, and chemoresistance, suggestive of unfavorable diagnosis. Of note, bacterial LPS trigger TLR activation of signaling pathways leading to uncontrolled hyperinflammatory state via IL-6, IL-1β, IFN–γ, and TNF-α enhancing the pathogenesis of bacterial infection-induced carcinomas including CC, gastric cancer, colorectal cancer, and lung cancers [40]. The overactivation of the inflammatory cells leads to the secretion of growth and survival factors, overexpression of extracellular matrix remodeling enzymes, proangiogenic factors, and other reactive oxygen species (ROS) which in turn facilitate the mutagenesis, tumor growth, and invasion [40, 140]. Different are the mechanisms in which TLR-regulated inflammatory response, inducing and enhancing the formation of cancer cells; probably the most known is the activation of the anti-apoptotic pathway through the NF-κB, considered a crucial transcription factor important in inflammatory conditions, that promote damages to DNA transcription whilst inhibiting repair responses [138,139,140]. Intriguingly, findings confirmed the higher tear serotonin levels with high serious inflammation and cell apoptosis on the ocular surface in SSRIs rat depression model. The overall outcomes indicated high expression of TLR2, with disrupted corneal epithelial barrier, accompanied by intense inflammatory response on the ocular surface by increasing the tear serotonin levels followed with apoptosis of corneal epithelial cells [139, 140].

6.2 Epigenetic modification: mitochondria involvement and DNA methylation

Epigenetic modifications, including DNA methylation, mitochondrial defects, and chromatin alterations, can also impair immune responses during aging. Malik and colleagues confirmed a marked inhibition of H3K9 histone proteins in the elderly exhibiting an increased binding affinity to IFN type I and III promoters in myeloid immune cells such as the DCs, monocytes, and NKs [15, 133, 141] driving to a consequent deficit of IFNs production, particularly in the context of viral infections such as lung infection, UTI, skin and bone infection. Further investigation is essential to delve into intrinsic alterations within DCs in elderly subjects.

Intriguingly, it seems that mitochondria are involved in depressive disorder and are seen as the cause of some intracellular abnormalities due to the inhibition of some important functions such as, (i) the second messenger signal transduction cascade through the activation of 5HT and the estrogen receptor (ER) and, (ii) the dysregulation of monoamine receptors [142, 143]. While the specific antidepressant mechanism associated with a short-term increase in mitochondrial activity is well understood, long-term use has yet to be fully elucidated. Nonetheless, patients with mitochondrial disorders or with mitochondrial DNA (mtDNA) mutations, and polymorphisms often show typical symptoms of depression and anxiety. Of note, the ATP is the essential aspect that needs to be investigated whenever there is mitochondrial dysfunction. These observations stem from the simple mechanism linking ATP's essential role in binding neurotransmitters to receptors while meeting the energy demands of vesicle transport and neurotransmitter release [142, 143].

Both animal models and human studies have shown upregulation of mitochondrial activity, including cellular respiration, during acute antidepressant treatment, that decreases or remains substantially unchanged in chronic treatment [140,141,142,143,144]. Some studies have shown SSRIs as the most potent inhibitors of complex I and II + III activities and complex I-related respiration in mitochondria. SSRIs could interfere with mitochondrial electron transport chain (ETC) complexes and respiration and showed inhibitory properties against OXPHOS. The overall results have highlighted that antidepressants in general can be directly involved in several mitochondria dysfunction increasing the risk of neuronal adaptation and body homeostasis, especially at high and prolonged doses [143, 144].

6.3 The involvement of antidepressant drugs in different types of cancer in women

The empirical basis of the current hypothesis finds its conceptual foundation in the involvement of SSRIs and antidepressants such as benzodiazepines in some types of cancer such as BC, epithelial ovarian cancer (EOC) or lung adenocarcinoma (LAC) [145,146,147]. If we consider BC, for example, it has been confirmed that SSRIs play an important role in the pathophysiology. SSRIs are known to uncontrollably increase prolactin levels thereby interfering with the serotonin-estrogen axis; this condition is then exacerbated by the use of tamoxifen which induces a peri-post-menopausal state due to its inhibitory effects on estrogen [145,146,147].

In a large cohort of breast cancer patients, SSRI therapy was associated with a 27% increase in breast cancer mortality, which corresponds approximately to the total percentage of women diagnosed with CC and who received treatment with the same therapy during the pre- and post-menopausal period [148]. This seems likely since it has often been overlooked when limited to patients with prior depression or when comparing SSRIs to other antidepressant medications. Therefore, the proposal of a further possible cause of increased mortality from CC among SSRI users should not seem like a statement far from reality as it could be related to already known and verified pathophysiological effects, which could occur through a common process neuro-immuno-endocrine. route [148].

The mechanism by which SSRIs tend to influence prolactin secretion is not yet clear, although some proposals have been put forward; (i), serotonin indirectly modulates prolactin secretion through postsynaptic 5HT1A, 5HT1C/2, 5-HT2, 5-HT2C and 5HT3 receptors leading to increased prolactin secretion; (ii), serotonin inhibits the GABA interneuron and this leads to a weakening of the inhibition of dopaminergic action on prolactin, resulting in an increase in prolactin secretion; (iii) we have proposed a third way, according to which the increase in prolactin is associated with a decrease in serotonin due to the decrease in estrogen as a consequence of two intrinsically biological factors, menopause and intestinal/cervicovaginal dysbiosis also due to prolonged use of antidepressants (Fig. 3) [148, 149].

Fig. 3
figure 3

The complex and dynamics of cervicovaginal micro eco-environment. All the components rely in a multiphase interrelation in which SSRIs may eventually contribute to CC insurgence. Aging means significant structural and molecular changes that disturb the functional integrity of the whole system. Aging is linked to gut and vaginal epithelium permeability, making it more susceptible to environmental and epigenetic challenges, insults and allergens, leading to silent increasing inflammatory and immune reactions within the whole body. Mucosa cells from vagina and gut play a pivotal role in sensing and responding to different disturbing stimuli, through the release of cytokines and interleukins, including IL-1b, IL-6, and TNF-a which activate macrophages, NKs and DCs. which present antigens to T cells, thus initiating and modulating immune responses. Aging sees macrophages, NKs and DCs activation by mucosa-released cytokines eventually terminating to the generation of proinflammatory cytokines, contributing to chronic vagina and gut inflammation. Moreover, the epithelial barrier in the upper and lower tracts function as barrier but can also recognize Pathogen Associated Molecular Patterns (PAMPs) through Pattern recognition receptors (PRR) like Toll-like receptors (TLR) and NOD-like receptors (NLR), inducing the production of cytokines, chemokines and antimicrobial peptides (AMP) the mucosal release of chemokines such as CCL2 and CCL20, further activating macrophages, NKs and DCs and promoting the recruitment of inflammatory cells to the area. This sequence of events can result in the production of further inflammatory responses associated with the recruitment and activation of IFN-y with Th1 cells and M1 cells that induce non-tolerant responses, increasing susceptibility to local tissue damage and heightened antigen hyperresponsiveness, which manifest with hyperactive microorganisms, favoring pathogen settlement or chronic inflammatory disease in older individuals

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Of note, prolactin induces gene expression of estrogen receptor alpha and beta (ERα and Erβ), thereby promoting ERα activity in the absence of ligand; in contrast, estrogen has shown the ability to modulate prolactin expression through its estrogen receptor element (ERE) which can bind to ERα and ERβ. But what is most striking is that several results have confirmed the ability of estrogens to regulate the expression of the E6 and E7 oncogenes of SiHa cells as a consequence of the HPV16 (genotype) expressing ERE-like sequences in the promoter region and the nuclear estrogen receptor [148]. Therefore, an altered microbiome, a decay of both serotonin and estradiol that ultimately favor depression and anxious states is intrinsically linked to the silent presence of pathogens such as HPV responsible for deeper alterations in the tissue and muscular structure of the vagina (Fig. 4) [12,13,14,15,16].

Fig. 4
figure 4

How SSRIs can interact with the vagina/gut-brain axis, the HPA/HPG axis, and the possible consequences that may ultimately favor the development of CC. This association between factors affecting the vaginal microbiota has tremendous effects on vaginal homeostasis. The vaginal microbiota can be influenced by numerous factors beside the SSRIs including sexually transmitted infection, hormonal unbalance and contraception, menstrual cycle, ethnicity, sexual behaviors, hygiene practices, stress, nutrition etc. Those factors recruitment by influencing the vaginal microbiota will affect the local mucosa and epithelium which scatter uncontrolled inflammatory responses via TLRs with and pro-inflammatory cytokine production, T cell and neutrophil activation and maturation, subsequently affecting mood and CNS disrupting the HPA and HPG axis (Gargiulo and Nguyen)

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Therefore, it seems reasonable to indicate that SSRIs may ultimately play a non-negligible role in the onset of CC. Given the results of studies that have shown similar associations in drugs that affect prolactin levels, estrogen and serotonin metabolism, or that have an impact on the vaginal microbiota, it seems likely that confounding by indication has at least a crucial role in the involvement of antidepressants in the risk of CC in peri- and post-menopausal women [148, 149].

6.4 The logistic growth model is a possible way to predict the role of antidepressant drugs in the onset of CC

Although extensive and diverse detection measures have been adopted, the onset of CC cannot be stopped with screening tests alone. Earlier prevention of this tumor would be a life-saver due to the great invasive capacity of CC. Currently, computer vision, artificial intelligence, machine learning, exponential logarithms and algorithms are the most popular tools used to detect and predict various diseases [150,151,152]. Among them, different effective growth logistic models attracted great attention by rapidly detecting and predicting targeted diseases. Suitable algorithms can be applied to the targeted disease dataset that has been preprocessed by applying different preprocessing tasks such as data cleaning, variabilities reduction, and co-factors selection (Fig. 5) [150,151,152].

Fig. 5
figure 5

Graph showing the possible logistic growth model that can be used in the case of CC and SSRIs assumption during peri-post-menopause

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Cancer in general, CC in particular, can be considered an epidemic that spreads more or less rapidly in a population group (for example a group composed of peri-post-menopausal women) with a speed that depends on several factors: age, dysbiosis (intestinal/vaginal), metabolic disorders, silent inflammatory processes, depression, and eventually consumption of antidepressant drugs such as the SSRIs [152]. The higher the number of women who are affected by all these factors and who are treated with antidepressant drugs, the greater the possibility that they will be diagnosed with CC, and the more women who are not affected by it, the more the number tends to grow [152]. These factors could make the logistic growth model suitable for studying and predicting the spread of CC. There is a maximum value for the number with a certain diagnosis, i.e. the entire population [150].

This is an important example of a function with different cofactors and variables involved, ft0 the initial population, L the carrying capacity, and r the growth rate. Each of these has a specific meaning that determines the shape of the graph, and in the case of ft0 and k growth coefficient, can be easily estimated using the graph. Since the maximum of our sample is 100% of cases (y), i.e. the entire female subpopulation of the community who can be diagnosed with CC, for which the limit value is L = 100. This model can allow us to predict that over a certain period of time, the number of women in menopause, with the above conditions (cofactors and variables) who have started SSRI drugs at t(x = 0) will have the possibility of developing CC at ft(x = 1, x = 2, x = 3…). Based on the current state of knowledge, these algorithms can only represent a first approximation model. More data should be collected to evaluate the relative influence of all cofactors. However, a general understanding of the growth rate helps address the problem. The general form of this type of function is:

$$f\left( t \right) = \frac{L}{{\left( {1 + e^{{ - kt + kt_{0} }} } \right)}}$$

t = the time (x axis); f(CC%) = percentage of cases (y-axis); L = the upper limit representing a theoretical maximum % of CC, carrying capacity; k = growth coefficient; t0 = start at which the trend begins to be observed; Note that we only used a growth factor k, it is expected that further studies can improve the model by adding more variables.

The advantage of the proposed score function is that the constant difference rate can be obtained from the growth logistic model. For example, there are two different individuals and the covariates are × 1 and × 2 respectively (Fig. 4) [150, 151]. This means that if the covariates between two individuals differ by one unit, which could be the use of SSRIs, then their log difference ratios differ by the coefficient β, which can also be used as a further explanation of the equation. The suggested equation is as follows

$$\log \left\{ {\frac{{F\left( {t|x_{1} } \right)/\left( {1 - F\left( {t|x_{1} } \right)} \right)}}{{F\left( {t|x_{2} } \right)/\left( {1 - F\left( {t|x_{2} } \right)} \right)}}} \right\} = \beta^{\prime } \left( {x_{2} - x_{1} } \right).$$

Although a wide range of pre-existing risk factors must be taken into account, it is difficult to fully control the effects of antidepressant drugs, partly due to considerable variability in recording the effects of severity in long-term therapy. However, these logarithms represent a theoretical model that allow us to obtain a number as close as possible to the number of women who could be affected by CC, considering the general population and the different conditions related to peri- and post-menopause, depression and use of SSRIs [152].

7 Conclusions

To conclude, evidence linking long-term prescribed antidepressant therapy to the onset of CC is still rare, but emerging. For convenience and simplicity, we have therefore proposed a scenario in which antidepressants such as SSRIs class may eventually favor the possible occurrence of gradual structural changes, both local and systemic enhancing dysbiosis, pathogens development, and inflammatory patterns, that eventually conduct to CC insurgence. The possible increase in inflammatory patterns linked to the presence of high levels of TLRs, with the consequent hyper-activation of T and B cells, DC, NK, neutrophils, macrophages (M1) and proinflammatory cytokines due to the prolonged use of SSRIs could be the right scenario towards the onset of important mutations and the possible involvement of SSRIs in the onset of CC. Indeed, the involvement of TLRs in the pathogenesis of neoplastic diseases is well known. However, some issues regarding the exploitation of the possible role of SSRIs in neoplastic diseases such as BC and CC still need to be adequately addressed. It is crucial to adequately evaluate the expression of TLR levels in patients undergoing long-term SSRI treatment, since some discrepancies still exist among researchers on this matter. The influence of some of the SSRIs on TLRs functionality in transformed cells goes far beyond simple NFκB activation and should be studied in the context of cervix environment with its stimulating nature and strong immunogenicity. An inverse linear association between the duration of SSRI use and the risk of CC incidence could be consistent as has been finely described for different typologies of cancer such as the BC. Discovering new polymorphic variables and their association with increased risk of CC and achieving a better understanding of the same has been a pioneering achievement in recent times. Given the highly interconnected nature of SSRIs, age, dysbiosis, hormones, pathogens, and inflammatory models such as TLRs and their signaling pathways, as well as their association with numerous physiological functions within the human body, it is critical to take a precise targeting. We hope that the contents and conceptualizations presented here stimulate further investigations on the effect of the choice of treatments and therapies precisely based on the expected results.