Fimmu 11 02161

REVIEW
published: 15 October 2020

doi: 10.3389/fimmu.2020.02161
Etiopathogenesis, Challenges and

Remedies Associated With Female
Genital Tuberculosis: Potential Role
of Nuclear Receptors
Shalini Gupta and Pawan Gupta *
Department of Molecular Biology, CSIR-Institute of Microbial Technology, Chandigarh, India
Extra-pulmonary tuberculosis (EPTB) is recognized mainly as a secondary manifestation of a

primary tuberculosis (TB) infection in the lungs contributing to a high incidence of morbidity
and mortality. The TB bacilli upon reactivation maneuver from the primary site disseminating
to other organs. Diagnosis and treatment of EPTB remains challenging due to the abstruse
Edited by: positioning of the infected organs and the associated invasiveness of sample acquisition as
Marco Rinaldo Oggioni,
well as misdiagnosis, associated comorbidities, and the inadequacy of biomarkers. Female
University of Leicester,
United Kingdom genital tuberculosis (FGTB) represents the most perilous form of EPTB leading to poor
Reviewed by: uterine receptivity (UR), recurrent implantation failure and infertility in females. Although the
Sunil Joshi, number of TB cases is reducing, FGTB cases are not getting enough attention because of a
University of Miami, United States
Jiezuan Yang,
lack of clinical awareness, nonspecific symptoms, and inappropriate diagnostic measures.
Zhejiang University, China This review provides an overview for EPTB, particularly FGTB diagnostics and treatment
Marielle C. Haks,
challenges. We emphasize the need for new therapeutics and highlight the need for the
Leiden University Medical Center,
Netherlands exaction of biomarkers as a point of care diagnostic. Nuclear receptors have reported role in
Yean Kong Yong, maintaining UR, immune modulation, and TB modulation; therefore, we postulate their role
Xiamen University, Malaysia
as a therapeutic drug target and biomarker that should be explored in FGTB.
*Correspondence:
Pawan Gupta Keywords: nuclear receptors, uterine receptivity, cytokine modulation, female genital tuberculosis, recurrent
[email protected] implantation failure, endometrium regeneration, extrapulmonary tuberculosis
Specialty section:
This article was submitted to
Microbial Immunology, INTRODUCTION
a section of the journal
Frontiers in Immunology Mycobacterium tuberculosis (M. tuberculosis) is an etiological agent that causes tuberculosis (TB),
Received: 29 January 2020
which is a health issue of global importance. TB profoundly exists in two forms, i.e., pulmonary
Accepted: 07 August 2020 and extrapulmonary. The most prevalent site of TB infection is the lungs; this is called pulmonary
Published: 15 October 2020 TB (PTB), where the bacilli are phagocytosed in alveolar macrophages and are contagious via
Citation:
Gupta S and Gupta P (2020) Abbreviations: EPTB, Extrapulmonary Tuberculosis; PTB, Pulmonary Tuberculosis; TB, Tuberculosis; FGTB, Female Genital
Etiopathogenesis, Challenges and Tuberculosis; RIF, Recurrent Implantation Failure; UR, Uterine Receptivity; ER, Endometrium regeneration; CM, Cytokine
Remedies Associated With Female modulation; LIF, Leukemia inhibitory factor; VEGF, Vascular endothelial growth factor; NR, Nuclear Receptors; TR4,
Genital Tuberculosis: Potential Role of Testicular receptor; PPAR, Peroxisome Proliferator Activated Receptor; PXR, Pregnane X Receptor; VDR, Vitamin D
Nuclear Receptors. Receptor; LXR, Liver X Receptor; PR, Progesterone receptor; LRH1, Liver receptor homolog 1; Nurr, Nuclear receptor related;
Front. Immunol. 11:02161. AR, Androgen receptor; COUP-TF, Chicken Ovalbumin Upstream Promoter; SF-1, Steroidogenic Factor; FXR, Farnesoid X
doi: 10.3389/fimmu.2020.02161 Receptor; IL, Interleukin.
Frontiers in Immunology | www.frontiersin.org 1 October 2020 | Volume 11 | Article 02161

Gupta and Gupta Role of Nuclear Receptors in FGTB
aerosol dissemination. TB bacilli can also disseminate to other This review highlights the major challenges of EPTB, especially
organs and causes extrapulmonary tuberculosis (EPTB). The FGTB, and necessitates the need for research efforts for effective
genital organs are also an important site for dissemination. biomarker discovery in FGTB. The objective of this review is to
Table 1 shows the distribution of TB cases at extrapulmonary introduce the diagnostic, treatment, and comorbidity challenges
sites (1). EPTB is mainly considered to be a secondary associated with EPTB and, in particular, FGTB and to raise
manifestation of the primary infection, which is rarely fundamental biological questions regarding the impact of FGTB
contagious; however, extrapulmonary involvement can occur on female fertility and on the major issues of endometrium
with or without PTB. The World Health Organization (WHO) regeneration (ER), uterine receptivity (UR), and cytokine
reported 7 million TB cases in 2018 of which 15% were EPTB modulation (CM). This review covers the current knowledge
(2). Additionally, approximately, 10%–50% of EPTB cases are of nuclear receptors (NRs), reported in regeneration, female
reported to also have pulmonary manifestation (3). The reproduction, and in the maintenance of pregnancy with
prevalence of EPTB significantly contributes to TB-related the aim of conceptually postulating that NRs should be
morbidity and mortality and is a leading cause of maternal explored in the diagnosis and combating of FGTB-associated
mortality. In a case study, the highest mortality rates are female infertility.
reported for meningitis TB (9.6%) and peritoneal TB (8.5%)
(4). Peritoneal TB and female genital TB (FGTB) are a threat to
human species propagation (5). Bacterial dissemination leading
to EPTB occurs majorly via three different channels, i.e., EPIDEMIOLOGY AND CLINICAL
hematogenous, lymphatic, and direct spread (6). Additionally, PRESENTATION OF FGTB: THE
producing new blood vessels through vascular endothelial SILENT RISE
growth factor (VEGF) can assist in bacterial dissemination (7).
Some rare modes of transmission include congenital FGTB is the most enigmatic form of EPTB, representing 15%–20%
transmission, accidental inoculation, therapeutic instillation, of EPTB cases (12, 13), and is responsible for poor UR, poor
and vaccination (8). The atypical presentation, paucibacillary endometrial adhesions, and recurrent implantation failure (RIF) in
nature, arduousness in procuring appropriate clinical sample, females (14). However, the exact proportion of FGTB is not
lack of awareness among clinicians, and poor sensitivity of known due to underreporting of cases, nonspecific symptoms,
conventional microbiological techniques in EPTB, particularly misleading clinical appearance, and lack of diagnostic measures.
FGTB, are challenges in diagnosis that further raise the cost due Additionally, in a case study, approximately 75.6% of patients’
to disability. EPTB cases are on the rise; however, there is still a cases evaluated for infertility were diagnosed with FGTB (15). It is
very extensive awareness gap compared to PTB (15% vs. 86%) highly concerning because the manifestations are asymptomatic,
(9). The aim of the WHO’s “end TB strategy” highlights the and by the time FGTB is diagnosed, it has already left an impact on
need for patient TB care and awareness programs in PTB (10). female fertility and morbidity. There is also a social stigma
However, the information on EPTB needs to be adequately attached to FGTB that causes it to be difficult for women to talk
addressed. FGTB, which represents the most perilous form of openly about it. FGTB is known to mainly cause primary infertility
EPTB, is steadily rising as one of the major causes of infertility in rather than secondary infertility (16); therefore, even after
females. Globally, about 5%–10% of infertile women are successful treatment, conception rates are very low (19.2%), the
reported to have FGTB (11). FGTB demands immediate success of pregnancy is very low (16.6%), and the birth rate is also
attention because of its low recovery rates and the increased extremely low (7.2%) (17, 18). The TB bacilli break out from the
abortion rates observed during recent years. Primary infection primary site of infection and reach the genital area generally
of TB in the genital tract of females, albeit rare, may occur if the through hematogenous spread (19). The most prevalent site of
partner has active genitourinary TB. Despite our current bacterial infection for FGTB includes the endometrium (50%–
understanding, it is vital that research into EPTB and 60%), fallopian tubes (95%–100%), ovaries (20%–30%), cervix
especially FGTB is increased as it is critical to enhance our (5%–15%), myometrium (2.5%), and vagina/vulva (1%) (19, 20).
knowledge of this disease in order to effectively combat it. FGTB causes caseation, adhesions, ulcerations, and complete
distortion of the cavity causing Asherman syndrome. The
clinical appearance of FGTB is generally called “the considerable
TABLE 1 | The bacterial manifestation reported at the surplus site and the
pretender” because it mimics ovarian carcinoma (21). FGTB
prepotency. represent various clinical symptoms of infertility (43%–74%),
oligomenorrhea (54%), amenorrhea (14%), dysmenorrhea (12%–
Extrapulmonary forms Occupied site of EPTB (%) Mode of spread 30%), abdominal pain (42.5%), menorrhagia (19%), dyspareunia
Lymph node TB 35% Direct (5%–12%), and postmenopausal bleeding (2%) (19, 22–25). The
Pleural TB 20% Hematogenous abovementioned clinical presentations arise because the ER
Meningitis TB 5% Hematogenous capability is compromised, which contributes to recurrent
Abdomen TB 3% Direct pregnancy loss and infertility (Table 2). All these symptoms
Miliary TB 8% Hematogenous
Bone and joint TB 10% Hematogenous
pertain to the endometrium, and its regeneration needs to be
Genitourinary TB 9% Hematogenous addressed and investigated. The key factors that modulate and
Others 10% exacerbate FGTB need to be identified.

TABLE 2 | Various forms of clinical presentations of FGTB are shown along with the patient is diagnosed with mental disturbance or is found to
signs and symptoms.
have lymphocytic pleocytosis (42). Due to the nonparticular
Extrapulmonary Clinical Signs and Symptoms symptoms, miliary TB and urogenital TB are often diagnosed at
infection presentation an autopsy (8, 43–46).
Being a paucibacillary disease, the diagnostic measures of FGTB
TB of endometrium Uterine leiomyoma Pyometra
Postmenopausal Irregular vaginal bleeding and
involve a combination of bacteriological confirmatory measures.
TB persistent leucorrhoea FGTB patients exhibit features of dysfunction of genital organs
Oligomenorrhoea Menstrual disturbance rather than any symptoms of infection. Repeatedly invasive
Amenorrhoea Menstrual disturbance techniques are utilized to acquire sufficient samples of body
Menorrhagia Abnormal vaginal discharge
fluids, tissues, or biopsies. FGTB diagnosis is mainly done
TB of cervix Ovarian carcinoma Postcoital bleeding
TB of vulva Tumor Bloodstained discharge through endometrial samples using microscopy (AFB),
TB of ovary Perioophoritis Tubo-ovarian masses histopathological detection of epithelioid granuloma on biopsy,
TB of fallopian tube Salpingitis and Ectopic pregnancy and Gene-Xpert (41). Peritoneal fluid or biopsy for culture,
tubal block endoscopy, and cervical cytology are also performed for
Infertility Implantation failure
diagnosis. However, histopathological findings are not specific
TB of pelvic Fistula formation Rupture of a tuberculous pyosalpinx
Malaise Pelvic inflammatory disease for FGTB because of shedding of the endometrium. Magnetic
resonance imaging and positron emission tomography have been
used for detecting tubo-ovarian masses (47, 48). Loop-mediated
THE DIAGNOSTIC CHALLENGES OF EPTB isothermal amplification is the most convenient technique used for
WITH AN EMPHASIS ON FGTB diagnosing FGTB (49). A laparoscopy combined with
hysteroscopy is the most reliable tool to diagnose FGTB;
The diagnostic tools for EPTB include the nucleic acid however, this is associated with perioperative complications.
amplification test (Gene-Xpert), immunological test, biopsy, Laparoscopy is risky because of the presence of many adhesions,
body fluid examination, and sputum acid-fast bacillus (AFB) which cover the pelvic organs and may hinder the diagnosis and
smear. Gene-Xpert shows high sensitivity in EPTB samples but is can increase the risk of bleeding (41, 50). Hysteroscopy is
less in cerebrospinal fluid (CSF), i.e., 29% (26). The antibody- associated with various complications, such as excessive
based serological test has poor sensitivity and is not applicable to bleeding, perforation, inability to distinguish and distend cavity,
EPTB samples (27). Blood transcriptomic biomarkers are and flare-up of genital TB, which can cause abortions and
identified in TB, which can easily discriminate between healthy infertility (51). FGTB, specifically endometrial TB, represents
and infected persons (28–31). The onset of TB can be predicted ulceration, caseous necrosis, and hemorrhage; this necessitates
through metabolite changes in blood (32). Blood transcriptomic careful macroscopic sampling (51, 52). FGTB is a silent disease;
and metabolic signatures have improved diagnosis in TB and are rarely, it presents as abdominal pain, abnormal genital bleeding,
being explored as probable diagnosis for EPTB (8, 33, 34). and dyspareunia (53). The misdiagnosis rate is very high among
Systematic reviews on TB biomarkers, including antibodies, FGTB patients and is associated with several complications. The
cytokines, chemokines, proteins, and metabolic activity disease is mistaken for other gynecological conditions or
markers have already been published (35). These biomarkers, malignancy; for example, FGTB is misdiagnosed as ovarian
to some extent, have also been studied in EPTB (36, 37). EPTB is cancer or chocolate cyst or pelvic inflammatory disease (PID)
largely undiagnosed in patients, especially when visceral sites are (54), and FGTB patients who are reported to have cervical TB may
involved. The detection of EPTB, particularly FGTB, poses a masquerade as cervical cancer (41, 55). Additionally, FGTB
major challenge with conventional methods. EPTB diagnosis is patients may be mistaken or coexist with acute appendicitis or
challenging because of misdiagnosis, arduousness in acquiring of ectopic pregnancy (52). TB of the vulva and cervix is very arduous
clinical samples, being asymptomatic, and poor sensitivity of to distinguish as it appears as brucellosis, schistosomiasis,
existing diagnostic (Figure 1). Generally, miliary TB is tularemia, cervical amoebiasis, sarcoidosis, syphilis, or chancroid
misdiagnosed with systemic lupus erythematosus (SLE) (38). (56). Furthermore, a high level of drug resistance is witnessed in
EPTB, particularly peritoneal TB, may also be misinterpreted as FGTB (57). Given the above challenges with FGTB diagnosis,
ovarian cancer and peritoneal carcinomatosis (5, 39). Intestinal including exceptional positioning of organs, associated
TB is misdiagnosed with Crohn disease (40). Bone and joint TB invasiveness of sample collections, misdiagnosis, being
are misdiagnosed as rheumatoid arthritis, traumatism, and gout. asymptomatic, poor sensitivity, the emergence of drug resistance,
Vulva and vaginal TB is misdiagnosed with malignancy (41). and the lack of point of care, there is a strong need to identify
Invasiveness and constraints in obtaining biopsies prevent the FGTB-specific biomarkers. The biosignatures emanating from the
early diagnosis of EPTB, and in addition, these diagnostic tests pathogen have been reported for FGTB diagnosis (58). However,
can cause incidental damages and infection; for instance, in the the sensitivity of detection in FGTB patient samples is very low
case of meningitis TB, extraction of CSF can possibly harm the because the infected sites are missed due to the paucibacillary
nerves around the site of insertion. Biopsy, endoscopy, nature of M. tuberculosis. We are focusing on the host-derived
cystoscopy, and lumbar puncture are all performed depending biomarkers for the prompt and accurate diagnosis of FGTB from
on the case for other EPTBs (8). Meningitis TB is suspected when easily accessible samples without utilizing any invasive procedure.

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Gupta and Gupta

4
FIGURE 1 | Diagnostic challenges and remedies for EPTB, in particular FGTB. Various challenges associated with EPTB diagnosis, such as misdiagnosis, often asymptomatic and paucibacillary nature of bacilli,
lack of sensitivity of existing conventional methods, and lack of point-of-care diagnostics, lead to loss due to disability.
October 2020 | Volume 11 | Article 02161
Role of Nuclear Receptors in FGTB

TREATMENT CHALLENGES OF EPTB regenerative therapy to treat damaged endometrium, fallopian

WITH AN EMPHASIS ON FGTB tubes, and ovaries (41). Vitamin D plays a crucial role in the
treatment of FGTB (75). The use of steroids and immunotherapy
Treatment of EPTB faces major challenges from comorbidities is observed to a large extent among infertile patients and leads to
(e.g., HIV coinfection or renal failure), drug sovereignty, resurgence of M. tuberculosis (76). Surgery in FGTB is performed
misdiagnosis, drug disposition, and unusual positioning of a as an adjunctive therapy during persistent or recurrent infection,
few organs, i.e., endometrium, central nervous system (CNS) the presence of nonhealing fistulae, and for multi-drug-resistant
(Figure 2). Chronic renal failure exacerbates EPTB more than TB; however, reactivation of bacilli has been observed during
TB (59). During renal impairment, DOTS therapy is eliminated surgery and has been detected after hysterosalpingography,
by nonrenal routes; for example, by biliary secretion or through laparoscopy, hysteroscopy, and laparotomy (77). Obstetric
metabolism. Coadministration of anti-HIV and anti-TB drugs in complications, such as preterm labor, increased rate of
a comorbid condition leads to absorption issues due to a abortions, and neonatal mortality is high in FGTB. Perioperative
reduction in the assimilation of the two key anti-TB drugs complications, such as extreme hemorrhage with huge risk of
(rifampin and isoniazid) (60). Likewise, TB drugs also lower damage to the pelvic and abdominal organs and the bowel, have
the levels of antiretroviral drugs; as soon as the antiretroviral been discerned during laparotomy (41). FGTB with pervasive
therapy is initiated, it paradoxically results in worsening of adhesions in the uterus and blocked tubes and pelvis is not
symptoms or causes immune reconstitution inflammatory treatable even after successful treatment (41). Hysteroscopy is
syndrome (1, 61). A high proportion of drug-induced liver used to diagnose the adhesions and Asherman syndrome (78);
injuries are observed in cirrhosis patients coinfected with TB however, it is associated with several complications in FGTB, such
(62). Ascites formed in the body in peritonitis TB present a as, inability to visualize the cavity, excessive bleeding, perforation,
problem for anti-TB drug disposition (63). Approximately 10%– bowel injury, peritonitis, and flare-up of genital TB (51, 79).
20% of patients consuming ATT (anti-TB drugs; Ethambutol, Postoperative complications, such as bowel fistula and mortality
Pyrazinamide, Isoniazid, and Rifampicin) either in a single or rate are high in FGTB. Repeated invasive measures are required
combinatorial therapy are at a risk of evolving hepatotoxicity after ATT treatment for proper prognosis for fertility. The
(64–66). When EPTB is misdiagnosed as another disease, the conception rate after ATT is only 12.8%, and the outcome of
treatment for the erroneous disease may exacerbate EPTB; for pregnancy could still be a live birth, spontaneous abortion, or
example, immunosuppressant therapy given when EPTB is ectopic pregnancy (80, 81). Furthermore, if patients are considered
misdiagnosed as chronic kidney disease exacerbates the actual cured, their chances of pregnancy drop due to the irreversible
case of EPTB (67, 68). A case was reported in which damage of the fallopian tube and endometrium. Moreover, FGTB,
immunosuppressant therapy given for SLE in a patient if not properly treated, can cause permanent sterility through
coinfected with disseminated TB led to respiratory failure (69). endometrial destruction and tubal damage (41). In vitro
Meningitis TB treatment is challenging because of the poor fertilization (IVF) is considered to be the successful modality for
penetration of drugs (e.g., rifampin and streptomycin) into the pregnancy in FGTB patients; however, a pregnancy rate of only
CSF due to the impervious blood–brain barrier (70). EPTB is 17.3% is observed even after successful treatment (82, 83).
curable with ATT drugs only to an extent and may result in The emergence of drug resistance among EPTB, particularly
several complications; for example, patients on ATT treatment FGTB patients, is on the rise, and it poses a further threat to TB
may develop acute kidney injuries and increase the risk for control. EPTB patients have a higher proportion of drug resistance
nephrotoxicity neuropathy and CNS toxicity (71–73). EPTB compared to PTB patients (84). Furthermore, a high proportion of
treatment also has some exclusion criterion; i.e., chemotherapy drug resistance is witnessed among the treatment failure cases of
is detrimental during the first trimester of pregnancy as it EPTB (52.7%) and PTB (48.1%) (85). The emergence of a multi-
prompts pregnancy termination. Specific adjuvant therapy, drug-resistant strain has been reported in FGTB (57). Engineered
chemotherapy, and major surgery are suggested in some bacteriophages (Muddy, BPs33DHTH-HRM10, and ZoeJD45) are
uncommon types of EPTB to avoid the complications of TB used as an adjunctive therapy against drug-resistant disseminated
dissemination (Figure 2). Chemotherapy is required for Mycobacterium abscessus (86). Antitubercular peptides, such as
genitourinary TB with surgery being substantial and reconstructive cathelicidins, defensins, granulysin, and hepcidin, are developed as
surgery required to repair the ureteral strictures (3). novel TB therapeutics against drug-resistant TB (87).
The treatment of FGTB faces formidable challenges from
coinfection (HIV, etc.); drug toxicity; obstetric, perioperative,
and postoperative complications; reactivation; and emergence of
drug-resistant bacteria (Figure 2). FGTB and HIV coinfection GENITAL TUBERCULOSIS: ADEPTNESS
make the most deadly combination and is the leading cause of IN IMMUNE MODULATION
maternal mortality. Moreover, reactivation of bacilli has been
observed in FGTB and HIV coinfection (12). HIV-induced Various molecules that are essential for implantation are being
immunosuppression in FGTB patients may also cause PID (74). identified as potential players of uterine receptivity, such as growth
ATT drugs can cause several complications in FGTB (41). Stem factors, i.e., VEGF; cytokines, i.e., leukemia inhibitory factor (LIF)
cells, nanotechnology, and colostrum are being used as a (88, 89); and cell adhesion molecules, i.e., CDH1 (E cadherin),

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Gupta and Gupta

6
FIGURE 2 | Treatment challenges and remedies for EPTB, in particular, FGTB. Various comorbidity challenges associated with EPTB are depicted. The risk of EPTB, particularly FGTB, occurrence increases in a
comorbid condition depending on the severity of immunosuppression associated with these diseases. Coadministration of drugs results in drug sovereignty, toxicity, absorption issues, and paradoxical reactions in
the body, which can further exacerbate the condition. EPTB misdiagnosis and subsequent mistreatment suppress the immune system to such an extent that it increases the bacterial prepotency of spreading to
other organs (example genital organs) and exacerbation. Differential diagnosis in FGTB leads to erroneous surgical procedures, which can cause complications. ATT treatment in EPTB, in particular FGTB, faces drug
October 2020 | Volume 11 | Article 02161
disposition and accretion challenges. The unusual positioning of infected organs in EPTB illustrate treatment challenges, especially in meningitis TB, ovarian TB, urogenital TB, and endometrial TB. Due to the
inaccessibility of organs in FGTB, surgical interventions are required to avoid dissemination of M. tuberculosis; however, several perioperative complications have been observed during surgery. Erroneous surgical
Role of Nuclear Receptors in FGTB

procedures and mistreatment lead to obstetric and postoperative complications. Stem cell therapy, chemotherapy, vitamin D therapy, and surgical interventions can be beneficial in FGTB, whereas adjuvant therapy
is known to be effective in EPTB, and engineered bacteriophages and antitubercular peptides are used for drug-resistant TB.
ITGAVB3 (avb3), MUC-1 (Mucin-1), and MECA79, as well as contribute to the pathogenesis of EPTB; therefore, anti-VEGF
hormones expressed during implantation (90, 91) (Figure 3). FGTB agents are used in TB to prevent bacterial dissemination (96, 97).
infection is found to alter the endometrial milieu and, thus, the UR, TB bacilli show an antigonadotropic effect in FGTB, impeding the
by causing immune modulation, endocrine disruption, activation of production of progesterone and human chorionic gonadotropin
antiphospholipids antibodies, and microthrombosis, which leads to (98). In FGTB, luteinizing hormone (LH) and follicle stimulating
RIF, a major cause of infertility (92). FGTB significantly alters the hormone (FSH) levels are high, and inhibin levels are very low (99).
level of ITGAVB3, MECA79, CDH1, MUC-1, and VEGF, leading Inhibin is considered to be a more sensitive marker of ovarian
to RIF (90). ITGAVB3 is essential for implantation, and its reserve in FGTB compared to FSH (99, 100). Latent FGTB not only
expression is reduced in both FGTB and unexplained recurrent interferes with implantation in the basal endometrial layer, but also
pregnancy loss (90, 91). Additionally, an aberrant (reduced) lowers the level of two ovarian markers, i.e., antimullerian hormone
expression of LIF has been reported in the endometrium in and antral follicle count (101). Furthermore, it has been observed
FGTB. The concentration of LIF is higher in fertile women that FGTB lowers the oocyte yield and the ovarian reserve (101).
compared to infertile females (93). LIF can activate signal Cytokine production differs in PTB and EPTB patients; females
transducers and activators of transcription 3 (STAT3) through a with normal pregnancy have been observed to have Th2-type
signaling cascade mechanism, which regulates UR and is further cytokine milieu, whereas there has been shown to be an increased
required for the transcription of VEGF, an angiogenic factor whose production of Th1-type cytokines in unexplained recurrent
role during pregnancy is well studied (88, 90, 94, 95). FGTB lowers abortions (102, 103). The inflammatory environment in the
VEGF expression; thus creating an unfavorable environment for endometrium prompts the preponderance of adverse cytokines
embryonic implantation (90). On the contrary, high VEGF levels and antibodies of the Th1 repertoire, making it nonreceptive to
FIGURE 3 | FGTB: Immune dysregulation compromises female fertility. The impact of FGTB on female fertility is depicted. FGTB adversely affects uterine receptivity
through immune dysregulation. Various cell adhesion molecules, growth factors, glycoproteins, and cytokines mentioned here are potential biomarkers of uterine
receptivity and for successful placentation. FGTB lowers the level of CDH1, MUC1, MECA79, and ITGAVB3, leading to recurrent implantation failure. Similarly, FGTB
pares down the levels of VEGF and LIF, which are required for successful placentation, thus creating an unfavorable environment for embryonic implantation.
Glycoproteins and cytokines are also required for embryonic development. FGTB also affects embryonic development through upregulating proinflammatory cytokine
expression and antiphospholipid antibodies as well as by lowering anti-inflammatory cytokine expression and ovarian reserve markers, such as the antimullerian hormone.

the embryo, thereby causing an implantation failure (92). However, (Figure 4). NRs are ligand-activated transcriptional factors that act
T regulatory cells, a subset of CD4+ T cells limit the adaptive as molecular switches and can govern many physiological processes,
immune response and contribute to the persistence of chronic such as metabolism, reproduction, and development. The
infection. Immune dysregulation has been reported in patients who superfamily of NRs shares a common structure containing an
have a past or present history of EPTB as observed by an increased amino terminal domain, a conserved DNA-binding domain
production of T regulatory cells, high levels of IL-17, and (DBD), a hinge region, and a ligand-binding domain (LBD) at
CD4+ lymphocyte activation (104, 105). the carboxy terminal. The amino terminal domain includes the
activator function-1 region (AF-1), which interacts with several
coregulatory proteins and is also a site for various posttranslational
NRS AND FGTB: POTENTIAL MARKERS modification. The DBD is conserved and has two subdomains (for
AND DRUG TARGETS DNA binding and receptor dimerization), each containing 4
cysteine residues that coordinate with a zinc ion to form zinc
This review aims to accentuate three major points: (i) the diagnostic finger motif. The hinge region consists of a nuclear localization
and treatment challenges of EPTB, particularly FGTB; (ii) the need signal, and the LBD harbors another activation function domain
for new therapeutics and diagnostics of EPTB, particularly FGTB; (AF-2) that can interact directly with coregulator proteins (106).
and (iii) the demand for FGTB biomarkers as a point-of-care NRs can exist as monomer, homodimer, and heterodimer that
diagnostic. NRs appear to be major potential therapeutic targets recognize a specific DNA sequence on the target genes known as
owing to their roles being reported as both pro-TB and anti-TB response elements. NRs are classified into three categories based on
FIGURE 4 | NRs are potential therapeutic targets and markers. NRs have many roles in TB, which makes them potential therapeutic targets for combating FGTB.
NRs have been reported in female fertility; for example PR, VDR, COUP-TF, PPARs, SF-1, and LXR are essential for maintaining uterine receptivity through
successful placentation and embryonic development. NRs such as COUP-TF, VDR, ERb, and PPARs play an important role in differentiation of ovarian cells and
angiogenesis. NRs such as PR, ERb, PPARs, LRH1, and AR are reported in endometrium maintenance. NRs are also good immuno-modulators that may act either
directly to combat the compromised tissue’s regenerative capacity or indirectly via CM to repair damaged tissues. NRs such as AR, Rev-erb, TRa, FXR, and CAR
are reported for tissue regeneration, whereas PPARs, Rev-erba, Nurr77, Nurr1, PXR, FXR, RORa, and LXR are known to modulate different cytokines’ milieu.
Additionally, NRs enhance the self-renewing and differentiation capacity of transcription factors through direct modulation. NRs should be considered as TB
biomarkers owing to their reported roles in both therapeutics and pathogenesis. NRs such as TR4, PPARg, and PXR are considered as host cohorts in
M. tuberculosis survival. Conversely, NRs such as VDR, LXR, and Rev-erba are considered as good host combatants for M. tuberculosis clearance.

the ligand variability: class I constitutes the endocrine receptors, (LRH1), retinoic acid receptor (RAR), chicken ovalbumin
class II includes orphan receptors, and class III comprises adopted upstream promoter (COUP-TFII), steroidogenic factor (SF-1),
orphan receptors. The endocrine receptors recognize steroid androgen receptor (AR), LXR, VDR, progesterone receptor (PR),
molecules and vitamins as their ligands and possess a high estrogen receptor (ERb), and PPARs have been reported for
affinity toward them. The orphan receptors are those for which successful uterine implantation and endometrium maintenance.
no endogenous ligand has been deciphered, and the adopted VDR has also been reported to be important for the
orphans are those whose ligands have been recently identified, differentiation of granulosa cells. The NR LRH1 is reported to
and they bind to low-affinity dietary lipids. As various biological be important for mouse fertility (118), ovulation, and ovarian
processes are regulated by NRs, pharmacological inhibition or steroidogenesis (119, 120). RAR is involved in early embryonic
dysregulation of them can lead to various diseases, including development (121). COUP-TFII is required for placental
cancer, metabolic disorders, infertility, and neurodegeneration. development and angiogenesis (122, 123). SF-1 is reported for
They also play a significant role in infectious disease biology as folliculogenesis and in the process of ovulation with its absence
many pathogens, for their own advantage, can modulate NRs either in granulosa cells leading to impaired ovulation (124, 125). AR
by interfering with their transcriptional activity or by changing their signaling is essential for endometrial function, whereas its
function. NRs have been studied in macrophage response to perturbation leads to reproductive failure (126). LXR
infectious disease, which also shows the potential role of NRs in modulates ovarian endocrine and exocrine function and uterus
combating infectious disease (107). Our earlier studies show a contractility (127). VDR expression increases during pregnancy
heterologous and noncanonical ligand receptor pairing, which and helps with reproductive function (128). Vitamin D has roles
clearly demonstrates that M. tuberculosis engage NRs (108–110). in folliculogenesis, differentiation, luteinization, and
NRs, such as testicular receptor (TR4), peroxisome proliferator steroidogenesis as well as altering antimullerian hormone
activated receptor (PPARg), and pregnane X receptor (PXR), signaling and progesterone production (129). Vitamin D
enhance M. tuberculosis survival by subverting the host innate deficiency in pregnancy increases the fortuity of preterm birth
immune defense mechanism and may increase the risk of and preeclampsia (130, 131). PR signaling is essential for the
dissemination (108, 109, 111). Our group has shown that M. initiation and maintenance of pregnancy (132). ERb is essential
tuberculosis cell wall lipids can crosstalk with NRs, such as for maintaining the endometrium quiescence and vasculature
PPARg, TR4, and PXR. These NRs are involved in the formation (133). PPARs are essential for trophoblast invasion,
of lipid-enriched foamy macrophages inside the host cell, which decidualization, tissue remodeling, ovarian function, and
further enhances M. tuberculosis survival and subverts the immune placental formation (134–136). Additionally, circadian rhythm
response by abrogating the phagolysosomal fusion, inhibiting the disturbance is reported to affect female fertility (137). Rev-erb is a
secretion of proinflammatory cytokines and abating apoptosis. circadian NR, which maintains the circadian rhythm (138) and
Furthermore, our group also reports that PXR causes TB drug may have a role in female fertility. Because NRs play crucial roles
nonresponsiveness in human macrophages by virtue of modulating in female reproduction, they could make good therapeutic
drug efflux transporters (111). It has been observed that knockout of targets to combat female infertility.
PPARg in a mouse model reduces the growth of M. tuberculosis, RIF occurs due to compromised ER capacity; therefore, stem
lowers granulomatous infiltration, and enhances secretion of the cell therapy for ER could be helpful. Many NRs have gained
proinflammatory cytokines (112). Moreover, NRs, such as vitamin
D receptor (VDR) (113), Rev-erba (114), and liver X receptor
(LXR) (115), help with M. tuberculosis clearance. Interestingly, TABLE 3 | Role of Nuclear receptors in female reproduction.
EPTB patients with multidrug-resistant TB have lower vitamin D
Nuclear Functions in Female Reproduction
levels (116). TR4 is identified as a marker for early TB detection in
Receptors
rhesus macaques, demonstrating that NRs are likely to make good
biomarkers for TB (117). The expression level of TR4 is linked with LRH1 Essential for ovarian steroidogenesis and ovulation
severity of disease progression in the PBMCs of M. tuberculosis– PR Implantation, decidualization, and preventing endometriosis
ERa Endometriosis progression
infected rhesus macaques. Correspondingly, NRs can be modulated
ERb Maintenance of endometrium quiescence and vasculature
by small molecules, which allows them to be a potential therapeutic SF-1 Development of reproductive tissue, ovulation, and
drug target. NRs also may have a role in EPTB, particularly FGTB folliculogenesis
which needs to be addressed further. VDR Differentiation of granulosa cells, folliculogenesis, luteinization,
The three chief challenges pertaining to FGTB are UR, ER, and steroidogenesis
PPARa Proliferation and differentiation of ovarian cells
and CM. These three factors are required for maintaining female PPARb Implantation and decidualization
fertility; their dysregulation, either directly or indirectly, leads to PPARg Trophoblast invasion and placental formation, decidualization,
fertility issues. FGTB, either directly or indirectly, modulates UR and preventing endometriosis
and ER or CM, respectively; thereby, causing RIF. As mentioned AR Maintenance of endometrium physiology
RAR Embryonic development, growth, and reproduction
before, NRs also play multifarious roles in female reproduction
Rev-erb Regulating the circadian rhythm
and in sustaining viable pregnancies (Table 3). Any COUP-TFII Placental development and angiogenesis
perturbations in the expression of NRs could lead to LXR Control ovarian endocrine and exocrine function and uterine
spontaneous abortions. NRs, such as liver receptor homolog 1 contractility

attention in stem cell biology (139–142); estrogen receptor the M. tuberculosis components also relay their effect through
(ERa), PR, and PPARg are all implicated in endometriosis orphan or adopted orphan receptors.
(143–146); and AR, thyroid receptor (TR), farnesoid X
receptor (FXR), Rev-erb, and constitutive androstane receptor
(CAR) are reported in tissue regeneration (147–152). Female DISCUSSION
fertility is compromised due to endometriosis. NRs are known to
modulate endometriosis; for example, loss of PR expression leads Globally, EPTB and, in particular, FGTB are growing problems
to endometriotic tissue becoming resistant to progesterone, with increasing rates of morbidity and mortality worldwide.
leading to endometriosis (146). PR helps to relieve pain in FGTB represents the most perilous form of EPTB and is the
endometriosis by limiting inflammation and the growth of leading cause of infertility and recurrent implantation failure in
endometriotic tissue PPARs and retinoid X receptor alpha are females. FGTB cases are asymptomatic in early stages, and
expressed in abortive trophoblastic tissue and are upregulated in untreated FGTB can cause permanent sterility through
extra villous trophoblast in recurrent miscarriages (153, 154). endometrial destruction and tubal damage. FGTB diagnosis is
M. tuberculosis modulates various cytokines’ milieu, such as arduous because of varied clinical presentations, misdiagnosis,
interferon g (IFNg) and interleukin- (IL2) in the endometrium associated comorbidities, arduousness in acquiring of clinical
and TNFa, IL-6, IL-4, and IL-8 in the blood (155, 156). samples, poor sensitivity, it is often asymptomatic and
Additionally, administration of IFNg, TNFa, and IL-2 is paucibacillary, emergence of drug resistance, lack of point of
reported to cause abortions in pregnant mice (102, 157, 158). care, impenetrable sites, and abstruse positioning of the organs.
Moreover, IL-1b is shown to promote endometriosis Likewise, the treatment of FGTB faces formidable challenges due
and angiogenesis (159, 160). Conversely, IL-6 and IL-10 to drug toxicity; HIV coinfection; obstetric, perioperative, and
are reported to have increased production in normal postoperative complications; reactivation; and emergence of
pregnancy compared to spontaneous abortion (103). Various drug-resistant bacteria. Our review rolls out the possible
proinflammatory, anti-inflammatory, and pleiotropic NRs, such remedies to prevent FGTB by precluding several of these
as retinoic acid receptor-related orphan receptor, nuclear challenges and also highlights the need for exaction of
receptor related (Nurr) 77, Nurr1, RORa, PXR, FXR, PPARa, biomarkers in FGTB.
LXR, Rev-erba, and PPARs, are known as immune modulators It is imperative to understand that FGTB adversely affects UR
as they can modulate different cytokines’ milieu (114, 161–167). and causes immune modulation, which promptly leads to
LXR is known to inhibit proinflammatory cytokine expression abortions and also reduces the chances of conception. We
and is also responsible for maternal-fetal cholesterol transport; emphasize the imperative mechanism of FGTB-associated
there is also a reduction in LXR expression in miscarriages (168, female infertility by highlighting the three major challenges,
169). Additionally, FGTB modulates pregnancy-related i.e., UR, ER, and CM. FGTB adversely affects various
hormones, such as human chorionic gonadotropin and endocrine hormones (progesterone, estrogen, and human
progesterone, which are known to function via their cognate chorionic gonadotropin), cytokines, growth factors (LIF and
endocrine receptors (98). Taken together, NRs seem to be a VEGF), and cell adhesion molecules (ITGAVB3, MECA79,
promising target to combat FGTB by addressing the issues of CDH1 and MUC-1), which are responsible for the
UR, ER, and CM. Extensive knowledge about the expression and maintenance of successful pregnancy. We epitomize the need
function of the NRs in FGTB is lacking and needs to to identify the molecular switches at the interface of FGTB and
be addressed. mechanisms associated with female infertility.
FGTB modulates the localized endometrial immune Given the above challenges in FGTB, there is an exigent need
repertoire, which has been reported to modulate UR. There are to identify FGTB-specific biomarkers from accessible samples.
various reports illustrating the function of the endometrial NRs have been reported as both pro- and anti-TB but have
immune repertoire in recurrent spontaneous miscarriage (170), gained less attention in FGTB. They are reported to modulate
polycystic ovarian syndrome (171), endometriosis (172), and female fertility and stem cell plasticity and are also known as
unexplained infertility (173). Given the reported role of NRs in immune modulators. We attempt to invoke interest in the
the regulation of uterine implantation and CM as well as being exploration of NRs as a novel therapeutic target in FGTB-
cognate to pregnancy-related hormones, for example, estrogen, associated female infertility and as a potential biomarker. NRs,
progesterone, human chorionic gonadotropin, and human which are cognate to pregnancy-related hormones (estrogen,
placental lactogen, which function via estrogen receptor, PR, progesterone, and human chorionic gonadotropin) and have
and VDR, respectively (174–178), they are good potential targets been cited in female reproduction and regeneration, prompt us
to alleviate the disease. NRs could be excellent host-directed to postulate them as a potential player and target to combat
targets in FGTB as evident from previous reports of NRs in TB. FGTB-associated female infertility by addressing the issues of
M. tuberculosis can modulate the expression of NRs by certain UR, ER, and CM.
crosstalk with its lipid repertoire. It would be interesting to see The topic is of immediate importance because of the abrupt
whether M. tuberculosis components interfere or modulate the increase in disease severity, drug resistance, and lack of a
interaction of pregnancy-related hormones with their cognate knowledge base of the major diagnostic and treatment
endocrine receptors. It would be interesting to decipher whether challenges, which leads to exacerbation in FGTB. Although a

large number of biosignatures and mechanisms have been FUNDING

reported in FGTB, there is a paucity of specific targets and
biomarkers. Our review provides the conceptual advance; it This work was supported by the Council of Scientific and
postulates the role of NRs as a potential target and biomarker Industrial Research (CSIR) RC project (OLP115) to PG. This
in FGTB. The description is comprehensive and is factual. work is also supported by the Department of Biotechnology,
Fostering innovative research is required to (i) develop highly Ministry of Science and Technology, National Bioscience Award
permeable, safe, and nontoxic drugs with a novel mechanism of project (GAP-0162) to PG. We thank IMTECH, a CSIR
action and target; (ii) identify biomarkers and point-of-care laboratory, for the facilities and financial support. The funders
diagnostics; and (iii) develop a strategy to shorten the treatment had no role in study design, data collection, or interpretation or
regimens and reduce treatment-related functional disability. in any decision to submit the work for publication.
AUTHOR CONTRIBUTIONS
ACKNOWLEDGMENTS
SG and PG designed the study. SG and PG wrote the review. PG
contributed to the overall supervision of the manuscript. All authors We express regret for not citing the work of many our colleagues
contributed to the article and approved the submitted version. due to space constraints.
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Etiopathogenesis, Challenges and

Department of Molecular Biology, CSIR-Institute of Microbial Technology, Chandigarh, India

Extra-pulmonary tuberculosis (EPTB) is recognized mainly as a secondary manifestation of a

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Gupta and Gupta

Role of Nuclear Receptors in FGTB

TREATMENT CHALLENGES OF EPTB regenerative therapy to treat damaged endometrium, fallopian

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Gupta and Gupta

Role of Nuclear Receptors in FGTB

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large number of biosignatures and mechanisms have been FUNDING

REFERENCES 15. Namavar Jahromi B, Parsanezhad ME, Ghane-Shirazi R. Female genital

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