Commentary
In the United States, approximately 10% of women of reproductive age have received infertility treatment. The prevalence of infertility in developing countries is probably greater than 10%. 1 Among cases of infertility, about 50% are attributed to female factors, and 25% to male factors; 25% are unexplained. 2 The percentage of cases considered to be unexplained would be lower if laparoscopy were routinely included in the evaluation, since this procedure can be used to diagnose conditions that might otherwise go unrecognized, such as endometriosis and, as in the present case, tuberculosis.
Although genital tuberculosis is rarely the cause of infertility in areas where there is a low prevalence of tuberculosis, 3 it should be considered routinely as a potential cause of infertility in areas where the infection is endemic. The estimated prevalence of genital tuberculosis varies widely — from 2 to 25% — among infertile women in developing countries, depending on the geographic location and the case definition used. 4 , 5
Genital tuberculosis typically arises from hematogenous dissemination of a primary pulmonary inoculum to the fallopian tubes in women (causing salpingitis) and to the epididymis and testes in men (causing prostatitis, urethritis, and epididymitis). However, cases of tuberculous salpingitis resulting from local spread of enteritis or peritonitis have been reported. 6 Endometritis, cervicitis, and peritonitis occur by means of local extension from salpingitis or through hematogenous spread. Reactivation of genital tuberculosis occurs in two phases: an initial exudative phase, with ulceration of the fallopian-tube wall, and a secondary adhesive phase, during which large tubercles form thick perisalpingeal adhesions, leading to tubal obstruction. 7
As in this patient, the clinical presentation of genital tuberculosis is often subtle, and at least 10% of patients have no apparent manifestations of disease. The major symptoms and signs of genital tuberculosis in women are infertility, pelvic pain, and menstrual irregularities, including postmenopausal bleeding. 8 Constitutional manifestations of disseminated tuberculosis, such as fever, weight loss, and night sweats, rarely occur in patients with isolated genital tuberculosis. 6
The most common radiographic findings in cases of tuberculous salpingitis are scarring and blockage of the fallopian tubes, which have a “pipe stem” or “beaded” appearance; calcium in the pelvis; a distorted endometrial contour; and hydrosalpinx. However, these findings are not sufficiently specific to establish the diagnosis. 9 Endometrial biopsy can provide a definitive diagnosis; alternative sources of samples for acid-fast staining and culture include menstrual fluid and ascites. However, the low sensitivity of endometrial mycobacterial culture and microscopy (40% and 60%, respectively, in small studies) limits the usefulness of these tests in detecting tuberculosis. 3 A mycobacterial polymerase-chain-reaction assay of endometrial fluid or tissue can serve as a rapid adjunctive diagnostic tool. 10 In the absence of a definitive microbiologic study, the presence of a necrotizing granuloma strongly suggests a diagnosis of tuberculosis if there is no alternative explanation.
False positive reactions to a tuberculin skin test may occur after BCG vaccination or infection with nontuberculous mycobacteria. In persons from regions where tuberculosis is endemic, however, a positive skin test (as assessed on the basis of the size of the skin induration, immune status, and status with respect to the risk of exposure) should be considered to indicate a high likelihood of previous tuberculosis, especially if the vaccination was administered many years earlier, as was true in this patient. False negative results can occur in patients who are immunocompromised and in those who have severe malnutrition or active tuberculous infection or who have had subcutaneous rather than intradermal administration of a tuberculin skin test.
Interferon-gamma release assays of whole blood, such as the QuantiFERON–TB Gold (QFT) test (Cellestis) and the T-SPOT.TB test (Oxford Immunotec), quantify the release of interferon gamma by mononuclear cells exposed to M. tuberculosis antigens. Because the genes that encode these antigens (early secretory antigenic target 6 [ESAT-6] and culture filtrate protein 10 [CFP-10]) are absent in most mycobacteria other than M. tuberculosis , including M. bovis (used in the BCG vaccine), these tests are highly specific for M. tuberculosis and may be particularly useful in the assessment of patients who have had BCG vaccination. In a meta-analysis of the performance of these tests, the pooled average specificity for the detection of latent tuberculous infection was 97% with the QFT test and 92% with the T-SPOT.TB test. 11 An additional advantage of these assays is that they require only a single visit; tuberculin skin testing requires a second visit for evaluation of skin induration. The Centers for Disease Control and Prevention supports the use of the interferon-gamma release assay as a screening tool for tuberculosis exposure for all circumstances in which tuberculin skin testing has been used and is preferred for testing of patients who have had BCG vaccination or are unlikely to return for test interpretation. Further study is required to determine the role of these assays in evaluating children, immunocompromised patients, and patients with suspected active tuberculosis. 12
Tubal and endometrial scarring are well-recognized sequelae of genital tuberculous infection, but there is a lack of data from prospective studies assessing the efficacy of antituberculosis therapy and IVF on fertility in affected patients. In addition to mechanical factors, decreased ovarian reserve may contribute to infertility in women with tuberculosis. However, the mechanism underlying decreased reserve has not been clearly delineated, and the findings come from a single retrospective analysis of women with genital tuberculosis who required higher doses of exogenous gonadotropins to achieve ovarian hyper-stimulation than controls with tubal infertility from other causes. 13 A case report of congenital tuberculosis in an infant conceived by means of IVF in a woman with undiagnosed genital tuberculosis further underscores the importance of recognizing and treating this disease. 14
A careful history taking, with attention to the patient’s country of origin and foreign travel, together with the use of new strategies for the diagnosis of tuberculosis, can facilitate diagnosis of the disease in cases in which it is unexpected. This approach may also help infertile couples conceive.