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

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

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 (Horne *et al.,* 2009).

The oestrogen receptor is reportedly a dominant regulator of normal Fallopian tube development (Mowa & Iwanaga 2000) however; expression of the oestrogen receptor remains constant throughout the ovulatory cycle (Horne *et al.,* 2009).

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

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

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

Tubal Damage, Infertility and Tubal Ectopic Pregnancy:

only 0.5% in this cohort of women (Casari *et al.,* 2010).

**4.2 Upper genital tract infections** 

**ovaries)** 

including human papilloma virus infections (Verteramo *et al.,* 2009).

surgery and trans-vaginal oocyte retrieval for *in vitro* fertilisation (IVF).

infection in these women and this may contribute to their infertility.

*Chlamydia trachomatis* and Other Microbial Aetiologies 17

lymphatic system (Brook, 2002). Bacterial vaginosis has been associated with genital and obstetric infections, including PID (Catlin, 1992; Hay *et al.,* 1992; Soper, 1994), particularly in the presence of other sexually transmitted infections (Hillier *et al.,* 1996; Wiesenfeld *et al.,* 2002)

Gaudoin *et al.,* (Gaudoin *et al.,* 1999) reported a strong association between bacterial vaginosis and tubal factor infertility and in a study by Wilson and colleagues (2002) it was concluded that women with tubal infertility were three times more likely to have bacterial vaginosis than women with male factor or unexplained infertility. In a retrospective analysis of a population of 952 women investigated over two years, it was recently reported that the genital discharges of asymptomatic women with infertility consisted of an overgrowth of several aerobic bacteria especially *G*. *vaginalis* (19.7%), Enterobacteriaceae or Enterococci (12.1%) and *Streptococcus agalactiae* (8.6%) noting a prevalence of *C*. *trachomatis* of

The most frequent method of female upper genital tract infection is by ascension of members of the lower genital tract endogenous microflora, which may first cause disruption to the normal balance such as that seen in cases of bacterial vaginosis or vaginal candidiasis (Population Council, 2003). Following medical intervention, iatrogenic infections may result from the direct inoculation of microorganisms from the lower genital tract into the upper genital tract. Iatrogenic procedures associated with tubal ectopic pregnancy are tubal

Seminal fluid is also reportedly a mechanism of microbial transfer to the female upper genital tract. Furthermore, some microorganisms have the propensity to attach to the surface of spermatozoa, whilst others are obligate intracellular parasites within the spermatozoa *C*. *trachomatis*, *N*. *gonorrhoeae*, *Mycoplasma* spp., *Ureaplasma* spp., and *E*. *coli* have all been shown to adhere to the surface of spermatozoa or form intracellular inclusions within the spermatozoa (Friberg *et al.,* 1987; Hickey *et al.,* 2009; James-Holmquest *et al.,* 1974; Murthy *et al.,* 2009; Sanchez *et al.,* 1989; Wolner-Hanssen & Mardh 1984). Further, female partners of infected men with spermatozoa in their ejaculate had a significantly higher incidence of upper genital tract infection compared to infected men who have been vasectomised (Toth *et al.,* 1984). Interestingly it was recently reported that a significantly higher incidence of sperm-immobilizing antibodies (6.4%) was found in sera collected from 273 infertile women with a past *C. trachomatis* infection compared to that found in women without a past chlamydial infection (1.5%) (Hirano & Hoshino 2010). Thus, it may be that the production of sperm-immobilizing antibodies in infertile women is the result of a past *C*. *trachomatis*

**4.3 Infections of the female upper genital tract (the endometrium, Fallopian tubes and** 

It is becoming increasingly accepted that the female upper genital tract is not a sterile site, but likely in fact to be asymptomatically colonised or infected with microorganisms (Horne et al 2008; Wira et al 2005). Endometritis, a persistent inflammation of the endometrial lining, has been reported in up to 19% of women (Farooki 1967). Endometritis is frequently asymptomatic, but similarly to other gynaecological infections, endometritis has been shown to reduce conception rates (Feghali et al 2003; Taylor & Frydman 1996). Excessive

activity of tubal cilia, result in the partial or complete destruction of cilia, and alter the composition and viscosity of the tubal secretions. Within the Fallopian tube mucosa, the response to microorganisms is not uniform. Each species evokes an individual and specific response (Laufer *et al.,* 1984). For example, *E. coli* cells or lipopolysaccharide cause swelling of the ciliary tips followed by adhesions between shortened and swollen cilia in addition to shortened microvilli on non-ciliated cells (Laufer *et al.,* 1980; Laufer *et al.,* 1984). *C*. *trachomatis* infection of Fallopian tubes reveals patches of flattened cells mixed with cells with only a single elongated cilium (Patten *et al.,* 1990). The sexually transmitted pathogen, *N*. *gonorrhoeae* causes invagination in ciliated cells and loss of microvilli in non-ciliated cells (Draper *et al.,* 1980).
