Cervix

Development

As a component of the female reproductive system, the cervix is derived from the two paramesonephric ducts (also called Müllerian ducts), which develop around the sixth week of embryogenesis. During development, the outer parts of the two ducts fuse, forming a single urogenital canal that will become the vagina, cervix and uterus.^[14] The cervix grows in size at a smaller rate than the body of the uterus, so the relative size of the cervix over time decreases, decreasing from being much larger than the body of the uterus in fetal life, twice as large during childhood, and decreasing to its adult size, smaller than the uterus, after puberty.^[10] Previously, it was thought that during fetal development, the original squamous epithelium of the cervix is derived from the urogenital sinus and the original columnar epithelium is derived from the paramesonephric duct. The point at which these two original epithelia meet is called the original squamocolumnar junction.^{[15]: 15–16} New studies show, however, that all the cervical as well as large part of the vaginal epithelium are derived from Müllerian duct tissue and that phenotypic differences might be due to other causes.^[16]

Histology

Transformation zone mucosa, when the squamocolumnar junction has a gradual transition. It consists of a mix of stratified squamous epithelium and mucinous glands. H&E stain.

Histology of endocervix, with mucinous columnar epithelium and mucinous glands. H&E stain.

The endocervical mucosa is about 3 mm (0.12 in) thick and lined with a single layer of columnar mucous cells. It contains numerous tubular mucous glands, which empty viscous alkaline mucus into the lumen.^[4] In contrast, the ectocervix is covered with nonkeratinized stratified squamous epithelium,^[4] which resembles the squamous epithelium lining the vagina.^[17]: 41 The junction between these two types of epithelia is called the squamocolumnar junction.^{[17]: 408–11} Underlying both types of epithelium is a tough layer of collagen.^[18] The mucosa of the endocervix is not shed during menstruation. The cervix has more fibrous tissue, including collagen and elastin, than the rest of the uterus.^[4]

• 
  The squamocolumnar junction of the cervix, with abrupt transition: The ectocervix, with its stratified squamous epithelium, is visible on the left. Simple columnar epithelium, typical of the endocervix, is visible on the right. A layer of connective tissue is visible under both types of epithelium.
• 
  Transformation zone types:^[19]
  Type 1: Completely ectocervical (common under hormonal influence).
  Type 2: Endocervical component but fully visible (common before puberty).
  Type 3: Endocervical component, not fully visible (common after menopause).

In prepubertal girls, the functional squamocolumnar junction is present just within the cervical canal.^[17]: 411 Upon entering puberty, due to hormonal influence, and during pregnancy, the columnar epithelium extends outward over the ectocervix as the cervix everts.^[15]: 106 Hence, this also causes the squamocolumnar junction to move outwards onto the vaginal portion of the cervix, where it is exposed to the acidic vaginal environment.^{[15]: 106 [17]: 411} The exposed columnar epithelium can undergo physiological metaplasia and change to tougher metaplastic squamous epithelium in days or weeks,^[17]: 25 which is very similar to the original squamous epithelium when mature.^[17]: 411 The new squamocolumnar junction is therefore internal to the original squamocolumnar junction, and the zone of unstable epithelium between the two junctions is called the transformation zone of the cervix.^[17]: 411 Histologically, the transformation zone is generally defined as surface squamous epithelium with surface columnar epithelium or stromal glands/crypts, or both.^[20]

After menopause, the uterine structures involute and the functional squamocolumnar junction moves into the cervical canal.^[17]: 41

Nabothian cysts (or Nabothian follicles) form in the transformation zone where the lining of metaplastic epithelium has replaced mucous epithelium and caused a strangulation of the outlet of some of the mucous glands.^{[17]: 410–411} A buildup of mucus in the glands forms Nabothian cysts, usually less than about 5 mm (0.20 in) in diameter,^[4] which are considered physiological rather than pathological.^[17]: 411 Both gland openings and Nabothian cysts are helpful to identify the transformation zone.^[15]: 106

Fertility

The cervical canal is a pathway through which sperm enter the uterus after being induced by estradiol after penile-vaginal intercourse,^[21] and some forms of artificial insemination.^[22] Some sperm remains in cervical crypts, infoldings of the endocervix, which act as a reservoir, releasing sperm over several hours and maximising the chances of fertilisation.^[23] A theory states the cervical and uterine contractions during orgasm draw semen into the uterus.^[21] Although the "upsuck theory" has been generally accepted for some years, it has been disputed due to lack of evidence, small sample size, and methodological errors.^[24][25]

Some methods of fertility awareness, such as the Creighton model and the Billings method involve estimating a woman's periods of fertility and infertility by observing physiological changes in her body^{[citation needed]}. Among these changes are several involving the quality of her cervical mucus: the sensation it causes at the vulva, its elasticity (Spinnbarkeit), its transparency, and the presence of ferning.^[12]

Cervical mucus

Several hundred glands in the endocervix produce 20–60 mg of cervical mucus a day, increasing to 600 mg around the time of ovulation. It is viscous because it contains large proteins known as mucins. The viscosity and water content varies during the menstrual cycle; mucus is composed of around 93% water, reaching 98% at midcycle. These changes allow it to function either as a barrier or a transport medium to spermatozoa. It contains electrolytes such as calcium, sodium, and potassium; organic components such as glucose, amino acids, and soluble proteins; trace elements including zinc, copper, iron, manganese, and selenium; free fatty acids; enzymes such as amylase; and prostaglandins.^[13] Its consistency is determined by the influence of the hormones estrogen and progesterone. At midcycle around the time of ovulation—a period of high estrogen levels— the mucus is thin and serous to allow sperm to enter the uterus and is more alkaline and hence more hospitable to sperm.^[23] It is also higher in electrolytes, which results in the "ferning" pattern that can be observed in drying mucus under low magnification; as the mucus dries, the salts crystallize, resembling the leaves of a fern.^[12] The mucus has a stretchy character described as Spinnbarkeit most prominent around the time of ovulation.^[26]

At other times in the cycle, the mucus is thick and more acidic due to the effects of progesterone.^[23] This "infertile" mucus acts as a barrier to keep sperm from entering the uterus.^[27] Women taking an oral contraceptive pill also have thick mucus from the effects of progesterone.^[23] Thick mucus also prevents pathogens from interfering with a nascent pregnancy.^[28]

A cervical mucus plug, called the operculum, forms inside the cervical canal during pregnancy. This provides a protective seal for the uterus against the entry of pathogens and against leakage of uterine fluids. The mucus plug is also known to have antibacterial properties. This plug is released as the cervix dilates, either during the first stage of childbirth or shortly before.^[29] It is visible as a blood-tinged mucous discharge.^[30]

Childbirth

The cervix plays a major role in childbirth. As the fetus descends within the uterus in preparation for birth, the presenting part, usually the head, rests on and is supported by the cervix.^[31] As labour progresses, the cervix becomes softer and shorter, begins to dilate, and withdraws to face the anterior of the body.^[32] The support the cervix provides to the fetal head starts to give way when the uterus begins its contractions. During childbirth, the cervix must dilate to a diameter of more than 10 cm (3.9 in) to accommodate the head of the fetus as it descends from the uterus to the vagina. In becoming wider, the cervix also becomes shorter, a phenomenon known as effacement.^[31]

Along with other factors, midwives and doctors use the extent of cervical dilation to assist decision making during childbirth.^[33][34] Generally, the active first stage of labour, when the uterine contractions become strong and regular,^[33] begins when the cervical dilation is more than 3–5 cm (1.2–2.0 in).^[35][36] The second phase of labor begins when the cervix has dilated to 10 cm (4 in), which is regarded as its fullest dilation,^[31] and is when active pushing and contractions push the baby along the birth canal leading to the birth of the baby.^[34] The number of past vaginal deliveries is a strong factor in influencing how rapidly the cervix is able to dilate in labour.^[31] The time taken for the cervix to dilate and efface is one factor used in reporting systems such as the Bishop score, used to recommend whether interventions such as a forceps delivery, induction, or Caesarean section should be used in childbirth.^[31]

Cervical incompetence is a condition in which shortening of the cervix due to dilation and thinning occurs, before term pregnancy. Short cervical length is the strongest predictor of preterm birth.^[32]

Contraception

Several methods of contraception involve the cervix. Cervical diaphragms are reusable, firm-rimmed plastic devices inserted by a woman prior to intercourse that cover the cervix. Pressure against the walls of the vagina maintain the position of the diaphragm, and it acts as a physical barrier to prevent the entry of sperm into the uterus, preventing fertilisation. Cervical caps are a similar method, although they are smaller and adhere to the cervix by suction. Diaphragms and caps are often used in conjunction with spermicides.^[37] In one year, 12% of women using the diaphragm will undergo an unintended pregnancy, and with optimal use this falls to 6%.^[38] Efficacy rates are lower for the cap, with 18% of women undergoing an unintended pregnancy, and 10–13% with optimal use.^[39] Most types of progestogen-only pills are effective as a contraceptive because they thicken cervical mucus, making it difficult for sperm to pass along the cervical canal.^[40] In addition, they may also sometimes prevent ovulation.^[40] In contrast, contraceptive pills that contain both oestrogen and progesterone, the combined oral contraceptive pills, work mainly by preventing ovulation.^[41] They also thicken cervical mucus and thin the lining of the uterus, enhancing their effectiveness.^[41]

Cancer

In 2008, cervical cancer was the third-most common cancer in women worldwide, with rates varying geographically from less than one to more than 50 cases per 100,000 women.^{[needs update][42]} It is a leading cause of cancer-related death in poor countries, where delayed diagnosis leading to poor outcomes is common.^[43] The introduction of routine screening has resulted in fewer cases of (and deaths from) cervical cancer, however this has mainly taken place in developed countries. Most developing countries have limited or no screening, and 85% of the global burden occurring there.^[44]

Cervical cancer nearly always involves human papillomavirus (HPV) infection.^[45][46] HPV is a virus with numerous strains, several of which predispose to precancerous changes in the cervical epithelium, particularly in the transformation zone, which is the most common area for cervical cancer to start.^[47] HPV vaccines, such as Gardasil and Cervarix, reduce the incidence of cervical cancer, by inoculating against the viral strains involved in cancer development.^[48]

Potentially precancerous changes in the cervix can be detected by cervical screening, using methods including a Pap smear (also called a cervical smear), in which epithelial cells are scraped from the surface of the cervix and examined under a microscope.^[48] The colposcope, an instrument used to see a magnified view of the cervix, was invented in 1925. The Pap smear was developed by Georgios Papanikolaou in 1928.^[49] A LEEP procedure using a heated loop of platinum to excise a patch of cervical tissue was developed by Aurel Babes in 1927.^[50] In some parts of the developed world including the UK, the Pap test has been superseded with liquid-based cytology.^[51]

An inexpensive, cost-effective and practical alternative in poorer countries is visual inspection with acetic acid (VIA).^[43] Instituting and sustaining cytology-based programs in these regions can be difficult, due to the need for trained personnel, equipment and facilities and difficulties in follow-up. With VIA, results and treatment can be available on the same day. As a screening test, VIA is comparable to cervical cytology in accurately identifying precancerous lesions.^[52]

A result of dysplasia is usually further investigated, such as by taking a cone biopsy, which may also remove the cancerous lesion.^[48] Cervical intraepithelial neoplasia is a possible result of the biopsy and represents dysplastic changes that may eventually progress to invasive cancer.^[53] Most cases of cervical cancer are detected in this way, without having caused any symptoms. When symptoms occur, they may include vaginal bleeding, discharge, or discomfort.^[54]

Inflammation

Inflammation of the cervix is referred to as cervicitis. This inflammation may be of the endocervix or ectocervix.^[55] When associated with the endocervix, it is associated with a mucous vaginal discharge and sexually transmitted infections such as chlamydia and gonorrhoea.^[56] As many as half of pregnant women having a gonorrheal infection of the cervix are asymptomatic.^[57] Other causes include overgrowth of the commensal flora of the vagina.^[46] When associated with the ectocervix, inflammation may be caused by the herpes simplex virus. Inflammation is often investigated through directly visualising the cervix using a speculum, which may appear whiteish due to exudate, and by taking a Pap smear and examining for causal bacteria. Special tests may be used to identify particular bacteria. If the inflammation is due to a bacterium, then antibiotics may be given as treatment.^[56]

Anatomical abnormalities

Cervical stenosis is an abnormally narrow cervical canal, typically associated with trauma caused by removal of tissue for investigation or treatment of cancer, or cervical cancer itself.^[46][58] Diethylstilbestrol, used from 1938 to 1971 to prevent preterm labour and miscarriage, is also strongly associated with the development of cervical stenosis and other abnormalities in the daughters of the exposed women. Other abnormalities include: vaginal adenosis, in which the squamous epithelium of the ectocervix becomes columnar; cancers such as clear cell adenocarcinomas; cervical ridges and hoods; and development of a cockscomb cervix appearance,^[59] which is the condition wherein, as the name suggests, the cervix of the uterus is shaped like a cockscomb. About one third of women born to diethylstilbestrol-treated mothers (i.e. in-utero exposure) develop a cockscomb cervix.^[59]

Enlarged folds or ridges of cervical stroma (fibrous tissues) and epithelium constitute a cockscomb cervix.^[60] Similarly, cockscomb polyps lining the cervix are usually considered or grouped into the same overarching description. It is in and of itself considered a benign abnormality; its presence, however is usually indicative of DES exposure, and as such women who experience these abnormalities should be aware of their increased risk of associated pathologies.^[61][62][63]

Cervical agenesis is a rare congenital condition in which the cervix completely fails to develop, often associated with the concurrent failure of the vagina to develop.^[64] Other congenital cervical abnormalities exist, often associated with abnormalities of the vagina and uterus. The cervix may be duplicated in situations such as bicornuate uterus and uterine didelphys.^[65]

Cervical polyps, which are benign overgrowths of endocervical tissue, if present, may cause bleeding, or a benign overgrowth may be present in the cervical canal.^[46] Cervical ectropion refers to the horizontal overgrowth of the endocervical columnar lining in a one-cell-thick layer over the ectocervix.^[56]