Tubal fluid plays a critical role in providing the right environment for gametes traveling through the tube and optimizing circumstances for sperm capacitation and fertilization of the egg. In addition, in the past decade, evidence from in vitro fertilization (IVF) data has shed light over the role of tubal fluid in implantation. Specifically, IVF in patients with hydrosalpinx results in a ~ 50 % reduction in pregnancy rates compared with patients without tubal disease [4]. In patients in whom the diseased tubes have been surgically removed, pregnancy rates have improved back to control values [5, 6]. Follicular fluid (FF) has been shown to be toxic to embryos in vitro [7]. Tubal fluid is composed of electrolytes, specifically high levels of potassium and bicarbonate compared with plasma. In addition, glycoproteins, glucose, pyruvate, lactate, and 17 different amino acids have been identified in tubal secretions [8]. The concentration of glucose fluctuates with the menstrual cycle. Following ovulation , the concentration of glucose decreases tenfold [9]. Tubal lumen glucose concentration drops from 3.1 mM in the follicular phase to 0.5 mM midcycle [10]. Human and animal studies have shown that estrogen and progesterone modulate oviductal fluid secretion by the epithelium [11, 12]. Estrogen causes hypertrophy, maturation, and the differentiation of the ciliated phenotype in fallopian tube epithelial cells in vitro [13]. Conversely, progesterone causes atrophy and decreases secretory production during the luteal phase .

Tubal fluid also contains glycoproteins, which may have a role in early development of the oocyte and embryos, enhance adherence of spermatozoa to the isthmus of the fallopian tube, and improve fertilization . Prior to ovulation, an oviduct-specific glycoprotein (OSGP) has been identified to enhance sperm capacitation, bind to the zona pellucida, and facilitate sperm penetration [14]. Others have postulated that OSGP and other glycoproteins increase the viscosity of the oviductal fluid, which serves as a buffer for the embryo against osmotic changes in the luminal fluid and also as protection against immunologic factors [15].

Spermatozoa undergo capacitation and antigenic changes through exposure to the uterus and tubal fluid, containing copious amounts of β-amylase [16]. This step is followed by the acrosome reaction, hyperactivation, and successful penetration of the zona pellucida of the oocyte.

In conclusion, the delicate composition of tubal fluid plays a critical role in fertilization of the egg, as well as embryo development and transport to the uterus. Any disturbance in the production of tubal fluid due to an erratic hormone milieu, destruction of secretory cells by fibrosis, or infection could potentially lead to altered sperm and egg transport and fertilization .

It is unclear what proportion of acute episodes of salpingitis is subclinical. Many young women may experience no symptoms or a low-grade fever or nonspecific abdominal pain. Oftentimes, these women do not seek medical care or get misdiagnosed. Physicians should therefore have a low threshold for diagnosis and treatment of subclinical or “silent” salpingitis to prevent future ectopic pregnancies and infertility.

In the 9 months following HSG and/or laparoscopy in ovulatory women with patent tubes, patients with Chlamydia trachomatis IgG seropositivity have a 33 % lower conception rate compared with seronegative patients [17]. The changes caused by C. trachomatis are intraluminal, and histological changes have been observed by salpingoscopy and biopsies of luminal epithelium (Figs. 18.2 and 18.3). Normal architecture of the fallopian tube is lost as neutrophils invade the tubal plicae and cause edema and congestion acutely. Long-term sequelae include scarring, fibrosis, and loss of luminal folds, normal epithelium, and cilia [18]. In addition, antibodies from a chronic inflammatory reaction elicits an autoimmune response to release human heat shock proteins (HSPs) [19]. These human HSPs can have a negative influence on the developing embryo during tubal transport as well as during implantation.

Acute salpingitis is usually secondary to sexually transmitted infection by Neisseria gonorrhoeae, C. Trachomatis, Mycoplasma, streptococci, staphylococci, coliform bacilli, and anaerobes, which reach the tube usually directly from the uterus attached to sperm or by blood vessels or lymphatic drainage. Clinically, young women may experience fever, leukocytosis, and adnexal tenderness [20]. The tube is usually enlarged, erythematous, and edematous. There can be exudates and an associated tubo-ovarian abscess. Microscopically, there are numerous neutrophils, congestion, and edema.

Chronic salpingitis frequently goes unrecognized. In patients with no known antecedent history of sexually transmitted diseases (STDs), 35.9 % of them tested positive for C. trachomatis antibody titer and had tuboperitoneal abnormalities found during an infertility workup [21]. What is better to have: a diagnosed or an undiagnosed salpingitis? This is yet another question that has not been fully studied. While the acute salpingitis may be more severe, because of symptoms, it is usually promptly treated with aggressive antibiotics, thus allowing some tubes to heal without significant scarring, while others may not escape long-term damage. The undiagnosed and therefore untreated kind, on the other hand, may represent a lower level of inflammation, but it is yet to be determined whether it could more likely to cause permanent tubal dysfunction secondary to subtle chronic changes in tubal anatomy as well as contractile motility.

The chronically inflamed tube can become enlarged, distorted, or adherent to other pelvic organs. There can be hydro- or pyosalpinx in which the tube is full of fluid or exudates, respectively. Microscopically, the tubal folds may be shortened, blunted, or fibrotic (Fig. 18.3). There is a chronic inflammatory infiltrate and flattening of the epithelial lining (Fig. 18.4).

Since the isthmus is less than 1 mm in diameter compared with the ampullary portion, which is 1 cm wide, mucus plugs may represent a relatively common and frequently unrecognized underlying cause of unexplained infertility.

Histologically, endotubal isthmic plugs consist of casts of histiocytes mixed with endometrial stroma or mesothelial cells [22]. Several studies have observed isthmic secretions increase with estrogen exposure and decrease after ovulation as the corpora lutea forms. Hypotheses on the origin of these isthmic plugs include retrograde menstrual flow, a sign of early pelvic infection, or secondary to cyclical estrogen prior to ovulation .

There are several lines of evidence that mucus plugs may play a major role in unexplained infertility. In a study by Sulak et al. [23], the majority of fallopian tubes diagnosed as obstructed by HSG were found to have only a mucus plug. Successful tubal cannulation either through hysteroscopy or novy cornual cannulation may also be partially attributable to dislodging a mucus plug rather than dilating an obstructed tube [24]. Flushing of tubal plugs could be the reason why for many years it has been known that performing an HSG demonstrating tubal patency is associated with a relative increase in fecundability of up to 20 % [25]. In many patients, dislodging the mucus plug may be all it takes to reopen the sperm–egg highway. Unfortunately, identifying the presence of a mucous plug prior to dislodging it during an HSG is not possible.

Salpingitis isthmica nodosa, or SIN, is an old HSG diagnosis for a nodular proximal tubal occlusion. The fallopian tube has nodular thickening of the tunica muscularis in the proximal isthmus enclosing dilated glands, which causes complete obliteration of the lumen [26]. The incidence of SIN in healthy fertile women ranges from 0.6 to 11 %, with a mean age of 26 years, and predisposes patients to infertility and ectopic pregnancies [27, 28]. It is bilateral in 85 % of cases [29]. The etiology is unknown, but some hypothesize a postinflammatory effect [30]. On salpingoscopy , this entity may present with no apparent lesion or gray–white nodules up to 2 cm in size in the isthmic portion of the fallopian tube. Microscopically, one can see nodules, cystic and dilated tubal epithelium with hypertrophic muscularis, and normal tubes distally. SIN is considered a risk factor for ectopic pregnancy [31].

How relevant is the diagnosis of SIN in the IVF era? The incidence of SIN in women with an ectopic pregnancy is 10 % compared with 0.2 % in the control group [32]. Patients with bilateral SIN should not attempt repair since the success rate is extremely poor with a high risk of ectopic pregnancy, and these patients should be immediately referred to IVF.

Tuberculosis was probably at one point the most common reason of irreversible infertility in endemic areas, giving the typical lead pipe appearance on HSG. Genital tuberculosis involves the fallopian tubes bilaterally in 90 % of women [33]. The most common cause of granulomatous salpingitis is Mycobacterium tuberculosis or Mycobacterium bovis. Grossly, there is thickening and nodularity in the wall, serosal tubercles, or caseous luminal exudate. In severe forms, there may be adhesions between the ovaries and other organs in the pelvis. Interestingly, the ostium usually remains open in contrast to many other forms of chronic salpingitis. Histologically, the mucosa has caseating granulomas, inflammatory changes, and fibrosis. There are epithelial hyperplasia and Schaumann bodies. Other less common causes of granulomatous salpingitis include leprosy [34], Crohn’s disease [35], sarcoidosis [36], chronic pelvic inflammatory disease [37], endometriosis [38], pelvic radiation [39], and giant cell arteritis [40].

Patients who had an intrauterine device (IUD) are most at risk for actinomycosis of the fallopian tubes, a disease caused by the Actinomyces species such as Actinomyces israelii. It affects both tubes in 50 % of cases, which may spread to the ovaries [41]. It is estimated that 7 % of women using an IUD have colonization with an Actinomyces species on a cervical smear [42]. If a patient is asymptomatic, there is no need for antimicrobial treatment or IUD removal. However, if a woman with an IUD has pelvic symptoms and a positive cervical smear for A. israelii, they are four times more likely to develop pelvic inflammatory disease [43]. Diagnosis can be made with Pap smear, computed tomography-guided tissue biopsy [44], or laparoscopically with a culture from the fimbrial lumen or posterior cul-de-sac [45]. On gross inspection, there can be small yellow flecks composed of sulfur granules within the tubal lumen. Sequelae of this infection include fistula communication between bowel, bladder, or skin. Histological examination shows granules of gram-positive filamentous bacteria surrounded by purulent exudates [46].

Although rare, there have been case reports of granulomatous salpingitis caused by blastomycosis [47] and coccidioidomycosis [48]. These fungal infections usually present as a tubo-ovarian abscess with peritoneal nodules, and the organisms are identified microscopically.

Parasites such as Schistosoma haemotobium have been found to cause nodularity and scarring with the histological finding of characteristic ova surrounded by fibrosis. Pinworms caused by Enterobius vermicularis have been identified as nodular thickening in the tubal wall. They spread from anal infections to the genital tract. The characteristics include eosinophilic infiltrates, giant cells, granulation tissue, and fibrous tissue. Cysticercosis has also been reported in the tube, with its characteristic calcified larvae surrounded by granulomatous salpingitis [49].

Physiological salpingitis is a nonbacterial inflammatory reaction that can be found in women at the time of menstruation or the peripartum period [50]. Clinically, patients are usually asymptomatic. The diagnosis was made from routine analysis of tubes removed at the time of hysterectomy or sterilization. Histologically, there is edema, lymphatic dilation, and infiltration with polymorphonuclear lymphocytes in the tubal plicae [51]. However, unlike infectious salpingitis, there is no necrosis, ulceration, or bacterial infection. Menstrual debris causes an inflammatory reaction in the tubal epithelium and stroma, but rarely involve the muscular walls. There are no known long-term sequelae from physiologic salpingitis. However, women are more susceptible to pelvic infections during menses due to low estrogen, less cervical mucous to block ascension of bacteria, and the presence of this physiologic salpingitis could facilitate infectious spread [52].

Similar to endometriotic lesions of other pelvic organs, it is unclear how the involvement of the fallopian tube in endometriosis affects fertility in most cases . Only a full obstruction of both tubes or unilateral obstruction where the other tube is absent represents a clear association. However, such instances are uncommon. The most common site of endometrial foci in the fallopian tube is the serosa, but the myosalpinx and mucosa can also be involved [53]. Endometrial tissue may spread from the uterus to the isthmic portion of the tube along with mucosal changes such as obstructing endometrial polyps [54]. These intratubal polyps are associated with ectopic pregnancy and infertility, especially if they are bilateral [55]. In one review, the prevalence of intramural tubal polyps was 3.8 % in a group of infertile women, where 50 % had unexplained infertility [56]. The diagnosis can be made by HSG. The lesions are typically broad based, 0.1–1.3cm, pink to red, smooth protrusions from the mucosa. Microscopically, one can see non-functioning endometrium covering the polyp.

In addition to obstructing lesions, endometriosis causes elevated oxidative stress, increased immunologic factors, and changes in the hormonal levels in peritoneal and FF. Reactive oxidative species (ROS) produced by erythrocytes, macrophages, and apoptotic endometriotic cells induce oocyte degeneration, DNA damage , increased cell membrane permeability [57], and cell death [58]. ROS negatively impacts fertilization through increased DNA fragmentation in spermatozoa [59] and inhibition of the acrosome reaction [60]. Nitrous oxide (NO) is higher in patients with endometriosis from the presence of macrophages. NO is toxic to embryos and decreases sperm motility [61].

Endometriosis has also been shown to affect the sperm interaction with the tubal epithelium. The tubal ampulla binds significantly more spermatozoa in women with endometriosis leaving less freely motile spermatozoa for fertilization [62]. Another study found cilia to beat at a lower frequency when exposed to peritoneal fluid from women with endometriosis [63].

Endometriosis may impair fertilization and implantation through decreasing oocyte quality, decreasing sperm motility, and/or exposure of the gametes/embryo to toxic peritoneal and FF. The FF of women with endometriosis decreases sperm binding to the zona pellucida [64]. Women with endometriosis have decreased levels of vascular endothelial growth factor (VEGF), which has been associated with reduced embryo quality and implantation defects [65]. Increased levels of circulating immunoglobulins and complement deposits have been detected in the peritoneal fluid of patients with endometriosis. This local inflammatory cascade has been proposed to increase ectopic endometrial implants, promote its growth, and release free radicals .

There are increased E2 levels in peritoneal fluid that stimulates cycle-oxygenase-2 (COX-2) enzyme, which then upregulates prostaglandin E2 (PGE2) production. PGE2 stimulates aromatase expression in endometrial tissue, which then produces more E2 and continues a vicious cycle of proliferation and cytokine induction [66]. Specifically, interleukin (IL)-6, and IL-1a cytokine produced by endometrial and epithelial cells in response to E2, has been shown to decrease sperm motility within the uterus [67].

The impact of endometriosis on fertility is widespread and still has many unanswered questions. Even with fertility treatments such as IVF, pregnancy rates are lower in women with endometriosis compared with controls (tubal factor) [68]. Should these patients be treated like unexplained infertility, especially if the diagnosis was found incidentally? There is still no clear answer for targeted treatment. Differentiating mild from severe endometriosis may help stratify who should be offered laparoscopic treatment, expectant management , or immediate assisted reproduction techniques (ART). The current recommendations are to treat patients with mild endometriosis similarly to patients with unexplained infertility, especially when invasive surgeries have not been shown to have a better clinical outcome [69].