Ultrastructurally, the cervical mucus can be seen as a complex biphasic fluid with high-viscosity and low-viscosity components. It is a hydrogel composed of a low-molecular-weight component (cervical plasma) and a high-molecular-weight component (gel phase). The cervical plasma consists mainly of trace elements (zinc, copper, iron, manganese, selenium, sodium, and chloride ions), organic components of low molecular weight such as glucose and amino acids, and soluble proteins, such as albumin and globulins [12, 55, 56]. The gel phase consists of a glycoprotein network called mucin, presenting glycosylation variations according to the menstrual cycle, contributing to the changes in its physical properties. This extremely large macromolecule (about 10,000 KDa) is rich in carbohydrate content and is responsible for the high mucus viscosity [57]. The mucin macromolecules are thread-like and appear in long parallel bundles maintained by a peptide of 30 kDa. This peptide connects mucin molecules through disulphide bridges (S–S), thus forming mucin micelles of 100–1000 glycoprotein chains [55]. This system assembly, which varies both in diameter and arrangement, is called “micelle.” Collectively, mucin molecules form a complex of interconnected micelles, which comprise a lattice whose interstices are capable of supporting the low viscosity phase, which is predominantly water. Protein content is low in the intermicellar spaces of Es mucus. The very low viscosity of Es intermicellar fluid allows very rapid sperm migration [12, 58]. In type G mucus, no micelle formation occurs, but the long macromolecules form a large, three-dimensional, irregular, dense network that does not allow spermatozoa to penetrate (Fig. 16.2) [59]. These channels or spaces vary in size according to the type of mucus: 2–5 μm wide (Es type mucus), 1–2 μm wide (El type mucus), and 0.3–1 μm wide (type G mucus). Therefore, intermicellar spaces play a key role in sperm migration [12] .

Abnormalities of cervical mucus can result in infertility. For instance, chronic cervicitis is associated with alterations of cervical mucus. In this case, a different mucus pattern appears, defined as type Q by Odeblad, in which the mucus composition varies depending on the type, degree, and duration of the inflammatory process. The crypts releasing this type of secretion have limited response to hormonal stimulation [51, 60]. In acute inflammatory conditions, the crypts can also produce a serous type of secretion of low viscosity but with high leukocyte content, classified as type V, which is unable to maintain sperm vitality. Therefore, common infections of the cervix such as those caused by sexually transmitted microorganisms ( Chlamydia trachomatis, Neisseria Gonorrhea, Trichomonas vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum) may result in cervical hostility [12].

Women with cystic fibrosis (CF) are also unable to produce the watery and stretchy mucus needed for optimal sperm penetrability. CF is caused by a mutation in the gene for the protein CF transmembrane conductance regulator (CFTR). This protein functions as a channel which transports negatively charged particles (chloride ions) inside and outside the cells. The transport of chloride ions helps to control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucus. When the CFTR protein does not work properly, chloride (Cl⁻) is trapped inside the cells. Because chloride is negatively charged, it creates a difference in the electrical potential inside and outside the cell causing sodium to cross into the cell. As a result, water movement from inside to outside cellular compartments is decreased, leading the mucus to be more viscous and less watery thus harming the sperm transport . Along with a loss of Cl^– conductance, mutations of CFTR protein also impede bicarbonate (HCO₃ ⁻) transport. A HCO₃₋ rich alkaline pH environment is crucial for optimal sperm motility and capacitation. During the process of releasing highly condensed mucins from intracellular granules, calcium (Ca²⁺) and hydrogen (H⁺) cations must be removed to enable the mucins to expand by as much as 1000 times, forming extracellular mucus–gel networks. It is suggested that HCO₃ ⁻ is essential to normal mucin expansion because it forms complexes with these cations. Due to defective HCO₃ ⁻ secretion in CF, mucins tend to remain aggregated, poorly solubilized, and less transportable. It is tempting to consider that some cases of reduced fertility in females might be associated with putative mild mutations in this gene with consequent abnormal cervix-uterine mucus release due to inadequate HCO₃ ⁻ secretion [14, 61, 62]. An example of this condition is the report of two infertile sisters with significantly abnormal cervical mucus who were found to be compound heterozygote carriers of the CF ΔF508 and R117H/7T mutations [13].

Many exogenous factors can render the cervical mucus hostile to sperm and, therefore, be implicated in the pathophysiology of unexplained infertility [12]. Clomiphene citrate (CC) , frequently used to stimulate follicle growth and ovulation as a first line therapy in couples with unexplained infertility, can interfere with the cervical mucus. Clomiphene is structurally similar to estrogen, which allows CC to bind to estrogen receptors (ER) throughout the reproductive system. In contrast to estrogen, CC binds to nuclear ER for extended periods of time, that is, weeks rather than hours, which ultimately depletes ERs by interfering with the normal process of ER replenishment. Acting at the hypothalamic level, CC is effective in ovulation induction by inhibiting negative feedback of estrogen on gonadotropin release, leading to up-regulation of the hypothalamic–pituitary–adrenal axis that, in turn, serve to drive ovarian follicular activity. At the same time, CC exerts undesirable and unavoidable adverse antiestrogenic effects in the periphery (endocervix and endometrium). Several studies have described that CC has adverse effects on the quality and quantity of cervical mucus based on cervical mucus score, the value of which is debatable. Despite that, available evidence and accumulated clinical experience support the notion that any adverse antiestrogenic effect presents a significant obstacle for the largest majority of women treated with ovulation induction drugs [16–18, 63, 64]. Another drug that deserves attention is propranolol, which accumulates extensively in the cervical mucus after oral administration; its concentration is fourfold higher in the mucus compared with in the blood. Despite not affecting mucus production, propranolol accumulation may impair sperm motility by its direct effect on sperm membrane ion transport and energy production [19, 65–67]. Nicotine and its metabolite cotinine are secreted into the cervical mucus, and can be found in the mucus even of passive smokers [68, 69]. A retrospective study evaluating smoking histories of 901 women with infertility due to different etiologies and 1264 pregnant women admitted for delivery suggested that smoking is a risk factor for cervical factor infertility (relative risk = 1.7; 95 % confidence interval of 1.0–2.7); however, its mechanism of action is unclear [70]. It has been suggested that nicotine could have toxic effects on spermatozoa, but in vitro studies have noted that the harmful effects of nicotine and cotinine to sperm occurs in extremely high concentrations, not seen in the seminal plasma or cervical mucus of smokers [20, 71].