**2. Tubal factor infertility**

In the absence of functional Fallopian tubes, couples may only conceive through *in vitro* fertilisation procedures. Women with tubal factor infertility may be defined as women who have either (1) damaged/occluded Fallopian tubes or (2) have history of salpingectomy. Ectopic pregnancy is only relevant if the Fallopian tubes remain *in situ*. Previous studies

Tubal Damage, Infertility and Tubal Ectopic Pregnancy:

**3.2 Steroid hormones (oestradiol and progesterone)** 

and ultimately implantation (Horne *et al.,* 2009).

(Horne *et al.,* 2009).

*Chlamydia trachomatis* and Other Microbial Aetiologies 15

point of ovulation and the cumulus-oocyte-complex gently propelling the ovulated oocyte into the Fallopian tube toward the uterus (Lindblom & Andersson 1985). Transportation of the oocyte and then following fertilisation, the embryo, through the Fallopian tubes takes approximately 80 hours (Croxatto *et al.,* 1972; Croxatto *et al.,* 1978). Inhibition of oocyte capture by the Fallopian tube may result from microbial infections of the tube. The subsequent immune response can form adhesions on the fimbrial end of the Fallopian tubes

The Fallopian tubes undergo cyclical changes under the influence of the steroid hormones, oestradiol and progesterone (Critoph & Dennis, 1977) and Fallopian tube steroid hormone receptors are expressed in response to the ovulatory cycle (Pollow *et al.,* 1981). Changes in the steroid hormone expression within the Fallopian tube contribute to successful transport

Progesterone has an inhibitory effect in ciliary movement and tubal smooth muscle contractility, resulting in a reduction in contraction frequency (Paltieli *et al.,* 2000) and ciliary beat (Wanggren *et al.,* 2008), capable of causing delayed transport of the embryo and ectopic implantation. Horne *et al.,* (2009) reported a reduced expression of progesterone receptors in the Fallopian tubes of women with previous tubal ectopic pregnancies. They were also unable to detect expression of an oestrogen receptor on the Fallopian tubes from these same women when compared to Fallopian tubes from non-pregnant women. The alterations in steroid hormone expression in response to the ovulatory cycle were discordant in nonpregnant women, compared with those reported in women with tubal ectopic pregnancies

The oestrogen receptor is reportedly a dominant regulator of normal Fallopian tube development (Mowa & Iwanaga 2000) however; expression of the oestrogen receptor

Previous investigations have assessed the effect of oral contraceptives on the risk of ectopic pregnancy. The inhibition of fertilisation or ovulation resulted in a decreased incidence of ectopic pregnancy in women with vasectomised male partners, and in women prescribed combined oral contraceptives. In contrast, the incidence of ectopic pregnancy was elevated in women using progesterone only contraceptives, and highest in those women using progesterone only contraceptive and an intra-uterine device (Franks *et al.,* 1990). This may be due to the effect of progesterone on ciliary beat frequency or in the case of an intrauterine device; there is an increased risk of ascending infection by commensal microflora. Finally, the steroid hormones oestradiol and progesterone are growth factors or inhibitors for various microbial species. It has been suggested that the more frequent diagnosis of specific genital tract infections at various stages of the menstrual cycle is due to the

The most frequent cause of ectopic pregnancy is previous salpingitis (Lehner *et al.,* 2000). The predominant facultative pathogens identified in tubal fluid from women with salpingitis are coliform bacteria (Holmes *et al.,* 1980; Ledger *et al.,* 1994; Swenson *et al.,* 1974) and the predominant anaerobic species originate from the *Bacteroides* genera. Microorganisms and the immune response may result in scar tissue formation, alter the

remains constant throughout the ovulatory cycle (Horne *et al.,* 2009).

concentrations of each of these hormones (Sonnex, 1998).

**3.3 Salpingitis and alterations to the Fallopian tube luminal epithelium** 

or cause altered pelvic anatomy, which prevents the physical movement of the tube.

have concluded that salpingitis can accompany early intrauterine pregnancy, often with significant foetal loss (Lara-Torre & Pinkerton 2002; Yip *et al.,* 1993) but that upper genital tract infections do not always result in poor reproductive health outcomes (den Hartog *et al.,* 2006). PID, which is diagnosed in greater than 800,000 women each year in the United States is associated with Fallopian tube inflammation, which can lead to tubal factor infertility in women ranging from 5.8% and 60%, depending upon the microbial aetiology of disease and the number of recurrent infections (Soper, 2010; Westrom, 1980). A recent estimate, not including women with 'silent salpingitis' or asymptomatic infections was that the annual cost of caring for women with PID is US \$2 billion (Soper, 2010). PID is known to be caused by the sexually transmitted microorganisms *C*. *trachomatis, N*. *gonorrhoeae,* and *M*. *genitalium* as well as bacterial vaginosis-associated microorganisms consisting predominantly of anaerobic Gram-negative bacilli. Investigations into the levels of antimicrobial compounds in Fallopian tubes or antibodies in sera collected from women with ectopic pregnancy, suggest that immune responses to infectious agents may also predispose for this condition (Refaat *et al.,* 2009; Srivastava *et al.,* 2008).

#### **3. Fallopian tube function**

The Fallopian tube plays an essential role in gamete and zygote transport. In parallel with the endometrium, the Fallopian tube also undergoes cyclical changes in response to the steroid hormones oestradiol and progesterone, which alter morphology and the frequency of beating of the ciliary (Critoph and Dennis, 1977a).

The transport of gametes and embryos through the Fallopian tubes relies on contractions of the tubal musculature, ciliary activity and the flow of tubal secretions (Jansen, 1984). Distortions of the luminal architecture of the Fallopian tubes have been associated with tubal ectopic pregnancy, predominantly because of failure of the transport mechanisms to move the gametes/embryos through the tube and into the uterus prior to implantation (Mast, 1999). Microbial infection of the Fallopian tubes is one reason for alterations in the tubal epithelial lining. Tubal disease resulting in infertility is the result of an inflammatory process in or around the Fallopian tube (Mastroianni, 1999). The extent of tubal damage is dependent on the severity and duration of the infection. The disease spectrum ranges from complete tubal occlusion with hydrosalpinx to mild intraluminal adhesions (Mastroianni, 1999).

#### **3.1 Ovulation and oocyte capture**

After ovulation, follicular fluid is the major constituent of the Fallopian tube secretions. The overall composition and viscosity of the tubal secretions (including elevated levels of steroid hormones and prostaglandins) enhances the ciliary beat frequency (Blandau *et al.,* 1975). Ciliary beat frequency is different for each part of the Fallopian tube. Elevations in the progesterone concentration in tubal secretions result in a slowing of the ciliary beat to allow fertilisation to occur, however, if the progesterone levels are too high then deciliation occurs and the prolonged delay in ciliary beat may result in implantation of the embryo within the Fallopian tube mucosa (Diaz *et al.,* 1980).

Prostaglandins within the follicular fluid mix with the tubal secretions and also increase the contractility of the fimbriae and the tubo-ovarian ligaments (Morikawa *et al.,* 1980). A controlled, deliberate movement of the tubal fimbriae ensues, initiating contact between the

have concluded that salpingitis can accompany early intrauterine pregnancy, often with significant foetal loss (Lara-Torre & Pinkerton 2002; Yip *et al.,* 1993) but that upper genital tract infections do not always result in poor reproductive health outcomes (den Hartog *et al.,* 2006). PID, which is diagnosed in greater than 800,000 women each year in the United States is associated with Fallopian tube inflammation, which can lead to tubal factor infertility in women ranging from 5.8% and 60%, depending upon the microbial aetiology of disease and the number of recurrent infections (Soper, 2010; Westrom, 1980). A recent estimate, not including women with 'silent salpingitis' or asymptomatic infections was that the annual cost of caring for women with PID is US \$2 billion (Soper, 2010). PID is known to be caused by the sexually transmitted microorganisms *C*. *trachomatis, N*. *gonorrhoeae,* and *M*. *genitalium* as well as bacterial vaginosis-associated microorganisms consisting predominantly of anaerobic Gram-negative bacilli. Investigations into the levels of antimicrobial compounds in Fallopian tubes or antibodies in sera collected from women with ectopic pregnancy, suggest that immune responses to infectious agents may also predispose for this condition

The Fallopian tube plays an essential role in gamete and zygote transport. In parallel with the endometrium, the Fallopian tube also undergoes cyclical changes in response to the steroid hormones oestradiol and progesterone, which alter morphology and the frequency

The transport of gametes and embryos through the Fallopian tubes relies on contractions of the tubal musculature, ciliary activity and the flow of tubal secretions (Jansen, 1984). Distortions of the luminal architecture of the Fallopian tubes have been associated with tubal ectopic pregnancy, predominantly because of failure of the transport mechanisms to move the gametes/embryos through the tube and into the uterus prior to implantation (Mast, 1999). Microbial infection of the Fallopian tubes is one reason for alterations in the tubal epithelial lining. Tubal disease resulting in infertility is the result of an inflammatory process in or around the Fallopian tube (Mastroianni, 1999). The extent of tubal damage is dependent on the severity and duration of the infection. The disease spectrum ranges from complete tubal occlusion with hydrosalpinx to mild intraluminal adhesions (Mastroianni,

After ovulation, follicular fluid is the major constituent of the Fallopian tube secretions. The overall composition and viscosity of the tubal secretions (including elevated levels of steroid hormones and prostaglandins) enhances the ciliary beat frequency (Blandau *et al.,* 1975). Ciliary beat frequency is different for each part of the Fallopian tube. Elevations in the progesterone concentration in tubal secretions result in a slowing of the ciliary beat to allow fertilisation to occur, however, if the progesterone levels are too high then deciliation occurs and the prolonged delay in ciliary beat may result in implantation of the embryo within the

Prostaglandins within the follicular fluid mix with the tubal secretions and also increase the contractility of the fimbriae and the tubo-ovarian ligaments (Morikawa *et al.,* 1980). A controlled, deliberate movement of the tubal fimbriae ensues, initiating contact between the

(Refaat *et al.,* 2009; Srivastava *et al.,* 2008).

of beating of the ciliary (Critoph and Dennis, 1977a).

**3. Fallopian tube function** 

**3.1 Ovulation and oocyte capture** 

Fallopian tube mucosa (Diaz *et al.,* 1980).

1999).

point of ovulation and the cumulus-oocyte-complex gently propelling the ovulated oocyte into the Fallopian tube toward the uterus (Lindblom & Andersson 1985). Transportation of the oocyte and then following fertilisation, the embryo, through the Fallopian tubes takes approximately 80 hours (Croxatto *et al.,* 1972; Croxatto *et al.,* 1978). Inhibition of oocyte capture by the Fallopian tube may result from microbial infections of the tube. The subsequent immune response can form adhesions on the fimbrial end of the Fallopian tubes or cause altered pelvic anatomy, which prevents the physical movement of the tube.
