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www.wjpps.com Vol 5, Issue 10, 2016.
Dubey et al. World Journal of Pharmacy and Pharmaceutical Sciences
CERVICAL MUCUS HELPS IN THE FERTILIZATION IN WOMEN
Vivek Dubey*1, S. Mythirayee1 Rajan Kumar Tiwari1, Utkarsh Gaharwar1,
Muneesh Pal1 and Sreenivasan Reddy2
1School of Studies Neuroscience, Jiwaji University, Gwalior -474011, India.
2Depatment of Pharmacology, JIPMER, Pondicherry, India.
ABSTRACT
Cervical mucus plays a vital role in female fertility. Infertility is most
important factor arising in reproductive health. It helps in the sperm
migration through the female reproductive tract, biochemical and
morphological changes to sperm, and sperm egg interaction in the
oviduct. The causes of infertility can be found in maximum of cases,
while about of patients don’t know why they cannot conceive.
Secretion levels of cervical mucus decide the fertility and infertility in
mammals. The cervical glands proliferate under the influence of
oestrogen secreted during the follicular stage of the ovarian cycle . The
glands become longer as the follicular cycle progresses. The glandular
epithelial cells become larger and start to secrete mucus that is initially
thick and viscous. This watery cervical mucus helps the sperm to swim into the uterus to
fertilize the ovum. It plays role in the protection of the uterine cavity from pathogens and
controls survival and migration of sperm cells. At ovulation, oestrogens increase hydration of
mucus, which results in watery secretion with low visco-elasticity, allowing sperm cells to
penetrate .This review is an attempt to collect relevant knowledge about the structure and
production of cervical mucus and draws attention to cervical mucus effect on fertilization.
KEYWORDS- ovum, sperm, cervical mucus, fertilization, fertility, and infertility, oestrogen,
capacitation.
INTRODUCTION
Cervical mucus is required for fertility, because it adapt, filter, prepare, store and release
sperm for transport to the oviduct (isthmoampulary junction) for fertilization. Sperm cells are
incapable of survival and transport toward the ovum in the absence of sufficient levels of
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 6.041
Volume 5, Issue 10, XXX-XXX Review Article ISSN 2278 – 4357
*Corresponding Author
Vivek Dubey
School of Studies
Neuroscience, Jiwaji
University, Gwalior -
474011, India.
viveka3892@gmail.com
Article Received on
26 July 2016,
Revised on 16 August 2016,
Accepted on 05 Sept 2016
DOI: 10.20959/wjpps201610-7765
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Dubey et al. World Journal of Pharmacy and Pharmaceutical Sciences
mucus.[2] Cervical mucus has a priming effect on sperm movement and capacitation. It acts as
―filter" that selects and excludes the sperm cells with defective locomotive mechanisms.
Sperm migration through cervical mucus increases ability to undergo acrosome reaction.
The capacity of mucus to accept sperm cells depends on the composition of carbohydrate like
glycoproteins. Physical and chemical properties of cervical coins decide the sperm
penetrability, like changes in glycosylation or intra – and into molecular bonds of mucins, as
well as the environmental conditions, like. PH and HCO3- availability.[27]
In the case of bacterial infection mucinase activity may affect the mucus to promote the
sperm progression by changing the biochemical properties of the cervical mucus. It was
demonstrated that the presence of antibodies Helicobacter pylori in the cervical mucus can be
involved in female infertility.[1] This infection is more prevalent in individuals with fertility
disorders. Infected women have anti-H. Pylori antibodies in cervical mucus and follicular
fluid that may decrease sperm motility and cross react immunologically with spermatozoa,
conceivably hampering the oocyte/sperm fusion.[1]
Cervical mucus as a sign of ovulation
Cervical mucus is also an important element for estimating the time of ovulation. It has been
used by women from many nations and cultures to recognize the fertile phase of menstrual
cycle for the purpose of fertility awareness.[26] Fertility awareness allows understanding and
making informed decisions about reproductive and sexual health. It can help couples to plan
pregnancies as well as to avoid them. Being familiar with their own mucus pattern helps
women to detect gynaecological disorders and to consult a physician. Since such
gynaecological disorders may represent the cause of infertility, monitoring mucus
characteristics can be useful in detection and therapy of the cause of infertility.[27]
Cervical Mucus production per day
Several hundred glands in the endocervix produce 20–60 mg of cervical mucus a day,
increasing to 600 mg around the time of ovulation. 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
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prostaglandins.[9] 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.[21] 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.[8] The mucus has stretchy
character described as Spinnbarkeit most prominent around the time of ovulation.[11] At other
times in the cycle, the mucus is thick and more acidic due to the effects of progesterone.[21]
This "infertile" mucus acts as a barrier to sperm from entering the uterus[14] Women taking an
oral contraceptive pill also have thick mucus from the effects of progesterone.[21] Thick
mucus also prevents pathogens from interfering with a nascent pregnancy.[25] 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.[24] It
is visible as a blood-tinged mucous discharge.[3]
Observing the mucus in ovulation
Mucus flows from the cervix down the walls of the vagina and can be observed when it
reaches the vulva. You can learn to observe the changes in your mucus by becoming aware of
the wet, lubricate feeling produced by the mucus, and by observing the mucus itself at the
vulva.[21] This is called the Billing (fertility awareness) method, and is very useful in allowing
you to determine when you ovulate. Tests need to be done to assess whether the mucus is
normal or not. The doctor examines the cervix and the cervical mucus daily from about the
tenth day of the period. The mouth of the cervix is graded, depending upon how open it is;
and the mucus is graded for its amount; its stretch ability ("spinnbarkeit"); and its ability to
fern. For the ferning test, a small drop of mucus is placed on a glass slide and allowed to dry.
It should crystallize, forming branches which look very like fern leaves. These grades are
added to give an Insler mucus score.[12] Healthy cervical mucus is profuse in volume; very
stretchable (up to 10 cm in length); and ferns easily.
Cervical mucus affect sperm migration
In some women, the cervical mucus may prevent the sperm from moving freely into the
uterus. Such a barrier may be because of the following reasons.[11]
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There is not enough of it to allow the sperm to move easily
The mucus is too thick and sticky
The mucus is not compatible with the male’s sperm.
Cervical Mucus pH
The pH of cervical mucus was measured with pH Merck paper by 0-14 indicators. The pH
paper is dipped into the mucus cervix. The changing colour of the paper is compared to the
attached standard colour paper Mucus pH changes before ovulation and returns to the
previous level after ovulation. It is an important determinant of sperm-mucus interaction.
Influence of pH on the structure of the newly evidenced cumin globules was investigated by
lowering the pH of the ovulatory mucus sample to 6.[25] The result was a dramatic
modification of mucin structure with the disappearance of globules and appearance of a
network that closely resembles the pre-ovulatory mucus. Ovulatory mucus with low viscosity
and high sperm permeability can be transformed to the highly viscous mucus with no sperm
permeability by simple acidification. This finding minimizes the relevance of compositional
changes, but still does not nullify it.[23]
MUCUS SECRETION
Secretory epithelium
Endocervical glands are duct-lacking invaginations within the cervical stroma with openings
to the cervical canal. The lumen of the cervix and the endocervical glands is lined by a
columnar epithelium that secretes cervical mucus.[19] Ultrastructural analysis of endocervical
glands defined three cell types in the epithelium: sub columnar basal cells, mucus-secreting
cells and ciliated columnar cells.[5] The ciliated cells contribute to mucus production by ion
and water exchange activity, which modulates the hydration of mucin molecules.
Cytochemical studies with peroxidatic activity revealed two cell types of glandular cells, but
their functional difference was not explained.[7]
Histochemical, immunohistochemical and molecular studies demonstrated that endocervical
epithelium undergoes cyclic, estrogen or progesterone dependent changes.[22] Additionally,
there is a hypothesis that endocervical glands with different spatial distribution produce
different mucus types depending on estrogen stimulation. According to this hypothesis, the
glands located in the upper portion of the cervical canal would secrete less viscous mucus,
and the glands from the lower parts would produce more viscous mucus.[1]
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Mechanism of mucus secretion
Biosynthesis and assembly of secreted, gel-forming mucins takes place in the endoplasmic
reticulum and Golgi complex. Fully processed, folded, glycosylated, sulphated and
polymerized gel-forming mucins are stored in high amounts in large secretory granules that
occupy the majority of the cytoplasm in mucous cells.[24] Vesicles filled with mucus were also
found outside the mucus cells and were called exosome-like vesicles. Their role is not yet
fully understood. Although it is known that mucins may be secreted constitutively, by
exocytosis of granules or small vesicles, or via a regulated pathway by exocytosis of
granules, an exact mechanism how the mucins are organized in the secretory cells and how
they are released is unclear. As a process of exocytosis commences, the condensed mucin
macromolecules in secretory granules undergo abrupt swelling.[20] The theory that explains
the swelling mechanism by increased intragranular water content and diffusal motion of
mucin molecules is now replaced by the theory of charge repulsion of the mucin polyionic
residues.[17]
Changes in pH and calcium concentration affect mucin granules swelling. Hence, regulation
of Ca2+ and H+ concentrations in the cervical canal can influence mucin hydration and
viscoelastic properties of mucus. Indeed, the dominant ion in the secretory granules is
calcium.[11] Polyanyonic mucins are highly condensed within granules as a result of high
concentrations of Ca2+ and H+ that shield negatively charged sites on mucins from
electrostatic repulsion. Once the secretory pore is formed, Na+ ions enter the mucin granule,
and start Ca2+ ion replacement. Since, according to electroneutrality principle, two Na+ are
required for each Ca2+, the increased counter ions inside the gel raise the osmotic pressure,
water molecules move into the gel and the granules swell.[4] The process of removing the
shielding cations from mucins is more efficient if the cations are previously attracted by
HCO3-. The initial expansion allows enzymes to cleave intramolecular covalent crosslinks
and to complete the process of mucin unpacking. Additionally, HCO3− ions are crucial for
normal release of gel-forming mucins to form transportable mucus. In the absence of HCO3−,
mucus remains stuck within the crypts of the cervico-uterine epithelium, i.e. within the
lumens of the mucus glands.[20] Poor HCO3− secretion seems to be a component of low and
reduced fertility as in cases of women with cystic fibrosis. NaHCO3 vaginal douching reduces
the viscoelasticity of cervical mucus and improves the sperm penetration test and post coital
test.[21]
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Regulation of mucus secretion - role of cyclic hormones
There are many indicators of correlation between mucus production and cyclic hormones
level. Expression of MUC genes is shown to be in correlation to progesterone levels. Also,
the flow of water towards the cervical lumen, increased K+ and decreased Ca2+ in the cervical
canal, pH change and antibacterial effect of mucus follow estrogen level rise. However, direct
evidence and a mechanism of estrogen or progesteron regulation of mucus production is not
yet provided.[11]
Cyclic hormone regulation of mucus production is not a simple and straightforward action,
since mucus production comprises diverse intracellular and extracellular events. Thus,
estrogen effect on mucus abundance and viscosity should be a cumulative result of estrogen
dependent changes in mucin gene expression, water flow, ion exchange, pH, HCO3− supply,
glycosylation, mucinase activity and velocity of mucus secretion and decondensation.[20]
The events taking part in mucus production could be divided into "slow" and "fast" events.
Slow events are expression of mucin genes, mucin protein synthesis and glycosylation,
surrounding connective tissue swelling, etc. protein MUC5B level reaches its peak at least
one day after the mRNA levels peak.[21] On the other hand, mucin granules swelling and
mucin expansion occurs within seconds. If both events are regulated by oestrogen, then two
distinct mechanisms of oestrogen regulation should take place.
Estrogen receptors (ER), like other steroid receptors, are largely located in the cytosol.
Hormone binding to the receptors triggers their migration into the nucleus, dimerization, and
binding to hormone-response elements on DNA.[21] As a consequence, gene transcription is
initiated like that ofMuc5b. On the other hand, some estrogen receptors may associate with
cell membranes and induce rapid, nongenomic activation of downstream signaling pathways.
A candidate estrogen receptor that would mediate such nongenomic estrogen effect was
GPR30, an intracellular transmembrane estrogen receptor. Later, GPR30 was confirmed not
to be an ER, but that it could just facilitate membrane-initiated steroid signaling under limited
circumstances. Nevertheless, estrogen receptors that usually reside in the cytosol, can also be
located at the cellular membrane and form complexes with G proteins, striatin, receptor and
non-receptor tyrosine kinases. Estrogen receptor α is present in the human endocervix tissue.
Binding estrogen receptor α to striatin leads to rapid estrogen-induced increase of Ca2+ and
nitric oxide levels. Such non-genomic estrogen activity could be involved in regulation of the
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"fast" events in mucus production, especially those that regulate intracellular and
extracellular ion concentrations and pH.[11]
PERSPECTIVES
The final intention about the mucus research is find out the therapeutic approaches to prevent
infertility and infections of reproductive tract. Thus, we should try to be answered are:
―mucus features are required for its fertility?" and "How the mucus achieves those features?".
The cervical mucus structure and function is a mosaic that only partially answers the
questions. There is a consensus that biophysical properties of the mucus are responsible for
sperm penetrability and hence for the fertility. The conditions that have to be fulfilled to
achieve these properties are not yet defined. Emphasize the role of pH, while other authors
give priority to ion concentrations or water flow. Biochemical content of the mucus seems to
have minor contribution to fertility, but has an impact to protective properties of the mucus.
The investigations of the chemical and biophysical properties of the mucus in vitro are very
helpful for understanding of its function. Direct application of these understandings to control
the viscoelastic properties of mucus could be a useful fertility strategy, but its applicability is
questionable. Research of the mucus secretion and maturation in endocervical glands can
give more valuable data about the inner and outer factors that contribute to and regulate
mucus production. Those factors may be the targets of a possible therapy.
Cervical mucus secretion, regulation and variability are still almost unexplored field. This
review just indicated a few elements of cervical mucus regulation, but it does not comprise all
elements that could be involved in the regulation of endocervical epithelial activity. For
example, investigation of neurogenic activation or interaction between secretory and colliery
cells could give a new insight into mucus production regulation. About cervical mucus, more
thorough studies with clinical data are required to understand and to utilize this understanding
to improve therapeutic approaches in infertility treatment and reproductive disease.
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