Jacobson, Denise L. PhD, MPH*; Peralta, Ligia MD†; Graham, Neil M. H. MD, MPH*; Zenilman, Jonathan MD‡
CHLAMYDIA trachomatis is the most common bacterial sexually transmitted disease (STD). In women, chlamydial infection usually presents as cervicitis. Asymptomatic or mildly symptomatic infections occur in up to 70% of cases. Estimates of chlamydial infection range from 3% to 5% in asymptomatic women to 20% in women examined at STD clinics.1 Chlamydial infection is implicated in up to 30% to 50% of pelvic inflammatory disease episodes, many of which are subclinical.2,3 Pelvic inflammatory disease has significant reproductive sequelae, such as tubal infertility and ectopic pregnancy.
Oral contraceptive (OC) use and cervical ectopy have been associated with an increased risk of chlamydial infection.1 Cervical ectopy is defined as the presence of endocervical columnar epithelium on the ectocervix. C trachomatis preferentially infects columnar cells; thus, ectopy may increase exposure of susceptible cells to infection. Alternatively, presence of endocervical cells on the ectocervix may result in improved detection of C trachomatis.2 The increased risk of chlamydial infection with OC use has been hypothesized to be caused by induction of ectopy, an increased number of partners, or by a direct affect of OCs either on the genital immune response or on the susceptibility of host cells. The interrelationship of cervical ectopy and OC use is especially important to discern in young or adolescent females when ectopy is highly prevalent, chlamydial infection rates are highest, and when OCs are the most common pharmacologic intervention.
This review defines ectopy and summarizes the literature on the changes in ectopy due to exposure to endogenous and exogenous reproductive hormones at different stages in a woman's life, and describes how ectopy decreases over time by different processes. The understanding of the physiology of ectopy, which involves a complex interplay of morphology and histology, is crucial to the study of the effect of exogenous hormones on infection risk.
Review of Cervical Anatomy and Physiology
In this review, we use the following standard anatomical or histologic definitions: the uterine cervix superior to the vagina is termed the endocervix, whereas the inferior portion is termed the ectocervix (or portio vaginalis); the external os is the area where the endocervical canal joins the vagina, and the internal os is the area where the endocervical canal joins the endometrium.
The types of epithelia that line the two parts of the cervix are affected differently by estrogen and progesterone, and are susceptible to infection by different organisms. For example, columnar epithelium (typically on the endocervix) is susceptible to chlamydial and gonococcal infection, whereas squamous epithelium is susceptible to human papillomavirus infection.
A monolayer of columnar epithelium, which is composed of tall, mucin‐secreting cells, lines the endocervical canal and the underlying “glandular” structures. Unlike true glands, these structures are actually cleft‐like infoldings that develop when the surface columnar epithelium invaginates into the underlying stroma to increase surface area.4,5 When columnar epithelium extends out onto the ectocervix, it is defined by colposcopists as cervical ectopy; however, no strict definition exists (Figure 1).4,5 Basal to the columnar cells are several subcolumnar cells, or “reserve cells,” that multiply and differentiate into squamous epithelium, thereby replacing the overlying columnar epithelium under certain conditions in a process called squamous metaplasia.6
Well‐differentiated squamous epithelium line the vagina and part of the ectocervix. Normal, stratified squamous epithelium is arranged in three layers: (1) basal cells; (2) parabasal cells and intermediate cells; and (3) superficial (mature) cells. Intermediate cells and mature squamous cells do not divide.4 The three layers respond differently to hormonal stimulation. Estrogen induces proliferation, complete maturation of all layers of epithelium, and desquamation. Progesterone causes thickening of intermediate layers but does not lead to complete maturation. When the ratio of progesterone to estrogen is increased (e.g., during pregnancy or during the secretory phase of the menstrual cycle), intermediate cells predominate; however, when this ratio is reversed (e.g., during the proliferative phase of the menstrual cycle or during administration of exogenous estrogen), superficial cells predominate. Without such hormonal stimulation the squamous epithelium is largely undifferentiated or atrophic, and glycogen is absent.7
Developmental Aspects of Ectopy
The Squamocolumnar Junction
The original (neonatal) position of the squamocolumnar junction changes as a result of hormonal influences in utero, at puberty, during pregnancy, and after menopause. The endocervical mucosa is fixed to the muscular wall and is stable in length. Movement of the endocervix, including “glandular structures” and stroma, onto the ectocervix occurs when the underlying muscle wall increases in volume under the influence of reproductive hormones. Because of anatomical constraints, the only direction for expansion of the endocervix in this situation is downward onto the ectocervix. This results in exposure of the endocervical mucosa to the vaginal environment (cervical ectopy) (Figure 1).5,8
The position of the original squamocolumnar junction, which is determined in utero, has been studied at different ages and at different points in a women's life using autopsy specimens, biopsy specimens, and colposcopy. The findings are inconsistent, perhaps owing to the two techniques that are used. Histology may be more sensitive than colposcopy in detecting the original and the neosquamocolumnar junction. An abrupt transition from columnar to squamous epithelium is rarely seen because of the presence of a transformation zone where cells are undergoing change.6 These demarcations may not be evident from a colposcope or by unaided visual assessment.
Squamous Metaplasia and Squamous Epitheliazation
Cervical ectopy is decreased in area over time by two processes: squamous metaplasia and squamous epitheliazation (Figure 2). Squamous metaplasia is a normal and irreversible physiologic process in which ectocervical simple columnar epithelium is replaced by squamous epithelium. Multiple physiologic factors are involved. The lower pH (4.5) of the ectocervix most likely destroys the buffering action of the mucus that protects columnar cells.5,7,9,10 Metaplasia is most pronounced when the progesterone/estrogen ratio is high (e.g., during late fetal life, during pregnancy, with OC use).11
Squamous metaplasia is multifocal and begins in distinct areas within the columnar epithelium, usually around “gland” openings, where the histologic borders to the surrounding columnar epithelium are distinct. The process of metaplasia can be arrested and resumed at any stage for reasons that are currently unclear.5,12 These foci eventually fuse, remodeling the zone of ectopy. This squamous epithelium is virtually indistinguishable from original squamous epithelium on the ectocervix except for the presence of clefts or retention cysts (“glands”) in the underlying stroma, which remain from the time when the layer was composed of mucosal columnar epithelium.5
The area in which squamous metaplasia replaces columnar epithelium is termed the transformation zone. Hamperl8 identifies the original squamocolumnar junction by the “gland” furthest from the external os, which can be determined histologically but not always colposcopically. As metaplasia progresses, the transformation zone moves from the original squamocolumnar junction toward the external os, and the area of ectopy decreases. A new border, the neosquamocolumnar junction, is created between the squamous cells that result from metaplasia and columnar cells.
There is an additional process of cervical remodeling called squamous epitheliazation. Metaplastic epithelium cannot always be differentiated colposcopically from squamous epitheliazation (sometimes called ascended healing), which also remodels the ectocervix. Tongues of squamous epithelium from the native squamous epithelium of the portio are thought to grow beneath the adjacent columnar epithelium, which are then sloughed off.13 This process is thought to replace areas of true erosion, and to be a reactive change due to inflammation or regeneration.5 This epithelium does not originate from subcolumnar cells, as in metaplasia. It is unclear, however, the degree to which metaplasia and squamous epitheliazation independently modify the area of ectopy or to what extent low pH, hormones, trauma, chronic irritation, semen, and cervical infection initiate and maintain each of these processes independently. Thus, the effects of repeated or chronic infection with C trachomatis, for example, on decreasing cervical ectopy are unknown. If chlamydial infection is dependent on an area of susceptible tissue, then susceptibility could decrease with increased remodeling of the ectocervix.
The position of the neosquamocolumnar junction is especially important to recognize, because it aids in the location of the area of columnar epithelium on the ectocervix. This area decreases with age. It is also important for colposcopists looking for abnormal precancerous squamous tissue, which is most prevalent near the neosquamocolumnar junction.
The Cervix at Different Stages of Development
The cervix in fetal life. During late fetal development, the fetus is exposed to maternal hormones that are believed to stimulate hyperactivity of columnar epithelium and produce ectopy.7,14 In a postmortem examination of 88 female infants, the prevalence of columnar cells on the ectocervix (ectopy) was less frequent in premature infants (29%) than in infants younger than 1 month (68%).14 The decreased frequency of ectopy in the premature infants may be due to the unresponsiveness of immature tissue.14 Infants with ectopy exhibited more mucus production, reserve cell activity, and growth of the endocervix and ectocervix. This growth might explain the shift downward in the position of the endocervical columnar epithelium and related stroma onto the ectocervix. In another study, 70% of mature autopsied fetuses presented with the squamocolumnar junction located on the ectocervix.7 Maternal estrogen exposure is thought to increase metaplasia. A significant transformation zone with metaplasia was observed in 39% of fetuses born after 36 weeks, but was present in fewer younger fetuses.7 These observations illustrate the effect of hormones in producing ectopy and metaplasia early in life.
The cervix in childhood. The influence of maternal hormones on the cervical mucosa diminishes after the first month of life. With the loss of maternal estrogen and progesterone and low levels of endogenous estrogen throughout the prepubertal period, some investigators believe that the ectopy produced in late fetal life retracts into the endocervix within the first year of life. Histologic studies by Hamperl and Kaufmann8 showed that the most prevalent pattern in childhood was an endocervical position of the original squamocolumnar junction. Similarly, Sersiron15 found that none of the 2,210 infants or juveniles observed during gynecologic examination showed ectopy. Madile14 found that ectopy was more common in infants than in children (2 out of 3 infants versus 1 out of 3 children) and argues that retraction of the ectopy occurs because columnar cell activity is low, the portio vaginalis shortens, and the lengthening of the endocervical mucosa pulls the ectocervical mucosa upward.
In contrast, some investigators believe that the ectopy present at birth does not usually retract into the endocervix. Singer16 reported that the squamocolumnar junction was in an ectocervical position in 67% of premenarchal females examined postmortem using a colposcope. Prepubertal exposure to reproductive hormones in these females is unknown. Similarly, Coppleson et al12 found a lack of reversion of columnar epithelium into the endocervix. Linhartova17 found that the cervix shortens shortly after birth, but that ectopy observed microscopically is still present in 61% of females 1 to 13 years, albeit less pronounced than at birth; the prevalence of ectopy was lower among the older females. In summary, although investigators agree that ectopy is present at birth, there is disagreement about whether ectopy retracts into the endocervix in childhood or to what extent it might retract.
The cervix in adolescence and hormones at puberty. Significant hormonal events occur at puberty. Puberty is marked by a rise in secretions of luteinizing hormone followed by increased ovarian secretions of estrogen. The body and cervix of the uterus begin to increase in volume 2 to 3 years before menarche. Newly secreted ovarian hormones at puberty are believed to cause increased intracervical edema. Because of anatomical constraints, the enlarged endocervix can only expand downward and outward, which causes eversion, thereby exposing more endocervical columnar cells on the ectocervix. A zone of ectopy is thus created. During menarche, changes in the vaginal environment include a drop in pH, which stimulates metaplasia.7 Several histologic and colposcopic studies support the notion of ectopy occurring at menarche, resulting in a new position of the squamocolumnar junction.
Histology and colposcopy of the adolescent cervix. Ectopy is more common after puberty than in prepubescent females. Hamperl and Kaufmann8 found temporal changes in the positions of columnar and squamous epithelium on the cervix from childhood through early adulthood. Using histologic specimens, they found an equal percentage of 13‐ to 15‐year‐old females who had columnar cells on the ectocervix as females who exhibited no columnar cells on the ectocervix (an endocervical position of the squamocolumnar junction). However, younger females 9 to 11 years infrequently had columnar cells on the ectocervix (10%), whereas most women 21 to 23 years (90%) had an ectocervical position of the squamocolumnar junction. This finding illustrates the changes that occur around puberty.8 Similarly, in another study7 that examined colpophotographs of autopsied cervices, the frequency of females with the squamocolumnar junction within the endocervix dropped from 28% in females younger than the mean age of menarche to 12% in females older than that age. Histologic sections of the same specimens supported the colposcopic observations. Additionally, more columnar epithelium was found ectocervically in the postmenarchal than in the premenarchal females. In conclusion, adolescents have increased rates of cervical ectopy that are related to increasing hormone levels at puberty.
Ovarian hormones also stimulate metaplasia, probably through a direct effect on reserve cells and by lowering vaginal pH. In one study, postmenarchal women had greater amounts of recently formed metaplastic epithelium than premenarchal women, but the amount of mature epithelium of fetal origin was the same in both groups.7
Puberty is not the only event that appears to accelerate the process of metaplasia, sexual activity has been associated with increased metaplastic activity. Whether this results from exposure to semen, sexually transmitted organisms, or other factors is not known. Semen is an attractive hypothesis because it is alkaline and has many immunosuppressive effects that could, theoretically, promote progression of STDs in the female genital tract.18 In colposcopic photographs of virginal and sexually active adolescent women, the latter had a larger proportion of new metaplastic activity than virgins.12,16,19 The original metaplastic area remained equivalent in the virgins and sexually active females of the same age. These observations are supported by Gotardi et al,20 who found that older sexually active females were more likely to have atypical transformation zones. In contrast to the virgins whose atypical zones did not vary by age, the atypical zones were larger in the older age groups among the sexually active females. Atypical areas could indicate immature metaplasia, response to inflammation, or human papillomavirus infection, which is highly prevalent among adolescents. A report by Coppleson et al12 suggested that sexual activity might cause some retraction of the ectocervix into the endocervix because the total transformation zone area is smaller in sexually active adolescents. The researchers speculate that either factors in semen (prostaglandins) or muscular contractions during intercourse may promote this phenomenon. In summary, there appears to be an increase in the prevalence of ectopy at puberty exposing columnar epithelium on the ectocervix. The ectopy gradually decreases with increasing amounts of metaplasia stimulated by hormones, decreased pH, and sexual activity.
The cervix in pregnancy. During pregnancy, the endocervical epithelium is everted onto the ectocervix due to hyperplasia of the columnar epithelium and by hyperemia and stromal edema, both stimulated by reproductive hormones.7,11,21–23 Late in pregnancy, mechanical venous obstruction may be a factor. Severe hyperplasia resembles a polyp, which can protrude through the external os (microglandular hyperplasia).24–27 Larger eversions are associated with larger increases in volume of the cervix from distended columnar villous processes and an increase in fibromusculature.21
Eversion begins early in pregnancy and is most marked during the second and early third trimester. It is more pronounced in the primigravida than in the multigravida female. The process of metaplasia begins early in pregnancy in the primigravida female with exposure to the low vaginal pH. In multigravida females, metaplasia is mostly seen in the third trimester when eversion is also most common.28 Metaplasia also occurs on endocervical cells exposed through gaping of the pregnant cervical os, especially in multigravida females. Postpartum, the cervix diminishes in volume and the columnar epithelium frequently revert back into the endocervix.29 After pregnancy, it is uncommon to see evidence of lesions on the cervix due to delivery.7 Denuded areas appear to be replaced with squamous epithelium.7
The cervix in the childbearing years through menopause.
With age there are increasing amounts of mature metaplastic epithelium initiated by sexual activity, infections, or hormones (including elevated hormone levels during pregnancy), which therefore decrease the amount of ectopy.7
Menopause begins when the ovary can no longer release ova. Luteinizing hormone and follicle‐stimulating hormone increase in the absence of ovarian estrogen feedback. In the postmenopausal years, some investigators believe that there is retraction of the transformation zone into the endocervical canal because of the reduced or absent exposure to ovarian hormones.6,12,30 Pharmacologically, however, the cervix is still responsive. Three of six recently postmenopausal women experienced displacement of the squamocolumnar junction from an endocervical to an ectocervical position after mestranol and norethisterone were administered sequentially.31
Estrogen and progesterone receptors in cervical tissue. Estrogen and progesterone bind to specific high‐affinity protein receptors and estrogen‐responsive proteins in cervical tissue to regulate cervical growth and the production of mucus.
Endocervical columnar cells bind progesterone at high levels, especially during the follicular phase.32 In women taking combined OCs, progesterone binding occurs at levels equal to or above secretory‐phase levels.32 These cells have a high number of estrogen receptors without variance throughout the menstrual cycle, but the estrogen‐responsive or estrogen‐regulated protein is not found during either phase of the cycle.33–35 The type of mucus production changes with exposure to estrogen.
The proliferation and maturation of squamous epithelium is stimulated by estrogen, whereas progesterone inhibits complete maturation. The estrogen receptor and the estrogen‐responsive or estrogen‐regulated proteins are found with variability in basal, parabasal cells and in intermediate cells throughout the cycle and during pregnancy, with a small increase in receptors in the follicular phase.4,33–35 Progesterone receptors are present in the parabasal cells during the luteal phase and during pregnancy.4
Subcolumnar reserve cells and cells undergoing metaplasia are most likely responsive to both estrogen and progesterone. Estrogen receptors and estrogen‐responsive proteins were identified in subcolumnar reserve cells and cells undergoing metaplasia throughout the menstrual cycle and during pregnancy33–35; however, the estrogen‐responsive protein is seen more frequently during pregnancy.34 Progesterone receptors are found only during the luteal phase and during pregnancy.36 Metaplasia is most pronounced during pregnancy, which suggests an interaction of these hormones.
The cervix in hormonal contraceptive users and with hormone therapy. Hormonal contraceptives are categorized into oral (short‐acting) and long‐acting formulations. OCs are typically a combination of a progestin and an estrogen. Long‐acting contraceptive preparations include depot medroxyprogesterone acetate (DMPA), which is an injectable progestin, and levonorgestrel, which is a progestin implant.37
The gross appearance of the uterine cervix of OC users resembles the cervix during “early” pregnancy. Both groups exhibit hyperplasia and hypersecretion of endocervical glands, increased metaplasia and stromal edema, hyperemia, and ectopy.11,38–40 It is difficult to separate the effects of estrogen and progesterone on these processes. Compared with pregnant women in the third trimester and with women taking continuous progestin therapy, fewer OC users exhibited the aforementioned changes.11 Among the three groups, the changes were most common in pregnant women, and the differences were attributed to increasing progestin exposure. Because current OCs contain lower hormone levels, the extent of cervical changes may be less pronounced than those previously seen.
In epidemiologic studies, it is difficult to compare the effects of various OC preparations on cervical ectopy. In one epidemiologic study, Louv et al41 found that the amount of estrogen or the type of progestin formula in oral contraceptives did not increase the prevalence of ectopy differentially. Few studies have addressed the effects of oral contraceptives on an increase in the “area” of ectopy.42,43 No studies in the literature were found that addressed the effects of long‐acting progestin‐only contraceptives, such as DMPA, compared with combined estrogen and progestin formulas on the area of ectopy. Recently, the authors reported the results of a cross‐sectional study in adolescents that examined the association between OCs, DPMA, and ectopy, which was measured using computerized planimetry.44 Neither OCs nor DPMA was associated with ectopy. However, the transformation zone was larger among OC users and was smaller among DPMA users. Longitudinal studies are planned.
Cervical physiology is extremely complex and changes during different stages of development. Columnar cells of the endocervix protrude onto the ectocervix under the stimulation of reproductive hormones during late gestation, puberty, and pregnancy. Exogenous effects, such as hormonal contraception and sexual activity, also affect cervical morphology and physiology. The area of cervical ectopy undergoes changes over time through metaplasia and epitheliazation, whereby squamous epithelium replace columnar epithelium under the influence of low pH and repair. Cervical ectopy decreases with age as these processes progress.
Results of studies of the association between ectopy and chlamydial infection or other outcomes are conflicting. Relevant variables or confounders have not been adequately addressed across studies. In addition, misclassification of ectopy may be an important reason for discrepancies across studies because ectopy has not been assessed by standardized criterion and because the age and parity of participants vary. Furthermore, few studies have evaluated longitudinally the impact of estrogen or progestin use on changes in ectopy. Because chlamydial infection is the most common bacterial STD, especially among adolescents, and because the infection can cause significant reproductive sequelae, it is important to gain a better understanding of the etiology and evolution of ectopy at different stages of development.
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