Etiopathogenesis, Challenges and Remedies Associated With Female Genital Tuberculosis: Potential Role of Nuclear Receptors

Abstract

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 positioning of the infected organs and the associated invasiveness of sample acquisition as well as misdiagnosis, associated comorbidities, and the inadequacy of biomarkers. Female genital tuberculosis (FGTB) represents the most perilous form of EPTB leading to poor uterine receptivity (UR), recurrent implantation failure and infertility in females. Although the number of TB cases is reducing, FGTB cases are not getting enough attention because of a lack of clinical awareness, nonspecific symptoms, and inappropriate diagnostic measures. This review provides an overview for EPTB, particularly FGTB diagnostics and treatment challenges. We emphasize the need for new therapeutics and highlight the need for the exaction of biomarkers as a point of care diagnostic. Nuclear receptors have reported role in maintaining UR, immune modulation, and TB modulation; therefore, we postulate their role as a therapeutic drug target and biomarker that should be explored in FGTB.

Keywords: cytokine modulation; endometrium regeneration; extrapulmonary tuberculosis; female genital tuberculosis; nuclear receptors; recurrent implantation failure; uterine receptivity.

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.

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 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 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.

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.

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, ERβ, and PPARs play an important role in differentiation of ovarian cells and angiogenesis. NRs such as PR, ERβ, 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, TRα, FXR, and CAR are reported for tissue regeneration, whereas PPARs, Rev-erbα, Nurr77, Nurr1, PXR, FXR, RORα, 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, PPARγ, and PXR are considered as host cohorts in M. tuberculosis survival. Conversely, NRs such as VDR, LXR, and Rev-erbα are considered as good host combatants for M. tuberculosis clearance.