Histological Changes in the Cervical Cells
Associated with Hormonal Contraception
Wala M Elfatih Mahgoub1* and Ibrahim A Ali2*
1 Department of Anatomy, The National Ribat University, Sudan
2 Department of Physiology, The National Ribat University, Sudan
Submission:September 14, 2018 ; Published: October 05, 2018 ;
*Corresponding author: Wala Mohamed Elfatih Mahgoub AbdAlla, Department of Anatomy, Faculty of Medicine, The National Ribat University, Khartoum, Sudan; Email:firstname.lastname@example.org
*Corresponding author: *Ibrahim A Ali , Department of Physiology, Faculty of Medicine, The National Ribat University, Khartoum, Sudan; Email:email@example.com
How to cite this article: Wala M E M, Ibrahim A A. Histological Changes in the Cervical Cells Associated with Hormonal Contraception. J Gynecol Women’s Health. 2018: 12(2): 555833. DOI: 10.19080/JGWH.2018.12.555833
Around the world, contraception has been used, in one form or another, for thousands of years. Many women use it for extremely long periods of time during their reproductive lifespan. There are different types of contraception that could be used by women at different stages in their lives and no one method that suits everyone. There are different types of contraceptives such as; combined hormonal contraception, progesterone only preparations, intrauterine contraception and barrier methods .
The combined oral contraception (COC)-“the pill”- contains a mixture of two hormones a synthetic estrogen and a synthetic form of progesterone. It is estimated that at least 200 million women worldwide have taken COC since it was first marketed. The COC affects almost all the systems in the body such as the nervous system in form of mood changes and headache, the gastrointestinal tract in form of nausea and liver cirrhosis, the breasts in form of breast pain, vascular system in form of venous thromboembolism and hypertension, reproductive system in form of vaginal discharge and cervical abnormalities [1,2].
Progestin-Only Pills, often called “minipills,” inhibit ovulation in about 50 percent of women. Their primary mechanism of action is thickening of the cervical mucus. This effect occurs within hours of taking a progestin-only pill and peaks about four hours after the pill is taken .
The injectable contraceptives contain a progestin like the natural hormone progesterone in a woman and do not contain estrogen, and so can be used throughout breastfeeding and by women who cannot use methods with estrogen .
The subdermal implant (Implanon) is inserted subdermally under local anaesthetic into the upper arm. It releases the progestogen etonogestrel and lasts for three years and thereafter can be easily removed and another one could be inserted if requested . The cervix is the lower cylindrical part of the uterus; its internal aspect which is closed to uterus lined with simple columnar epithelium and the external aspect that bulges into the lumen of the vagina is covered with stratified squamous epithelium .
During the proliferative (estrogenic) phase of menstrual cycle where the endogenous estrogen reaching its peak proliferation and reconstituting the endometrium that lost during menstruation takes place. In this phase the epithelium lining of the endometrium changes from a single layer of columnar cells to psudostratified epithelium with frequent mitosis and the endometrial thickness increases rapidly from 0.5mm at menstruation to 2-3mm; while in secretory phase, progesterone induces the formation of a temporary layer, known as the decidua, in the endometrial stroma. Histologically, this is seen as occurring around blood vessels. Stromal cells show increased mitotic activity, nuclear enlargement and generation of a basement membrane. In this phase, the endometrium reaches its maximum thickness (5mm) as a result of the accumulation of secretions and edema in the stroma [1,5].
It is known that both estrogen and progesterone affect the differentiation and proliferation of the epithelial lining of the endometrial layer of the uterus during their menstrual cycle. Hormonal contraception depends upon administration of exogenous forms of either progesterone or both estrogen and progesterone, these exogenous hormones affecting the endometrial layer of the uterus in response to their steady concentrations of the blood especially for a long time .
Contraception, also known as birth control and fertility control, is a method or device use to prevent pregnancy. Contraception has been used, in one form or another, for many decades. Many women will use it for extremely long periods of time in their reproductive lifespan. Women use different types of contraception at different stages in their lives and there is no one method that will suit everyone. There is no perfect method of contraception and each method will have a balance of advantages and disadvantages. An ideal contraceptive method should be; highly effective, no side effects or risks and cheap .
There are many and different methods of contraception
including; combined hormonal contraception, among these there
are: the pill, patches and vaginal ring; the commonest method
used for lactating mothers is progesterone -only preparations,
which include, POP, injectables, and subdermal implants; also
there are hormonal emergency contraception and intrauterine
contraception which occurs in form of copper intrauterine device
(IUD) and hormone-releasing intrauterine system (IUS); barrier
methods are globally used and includes, condoms, female barriers
(fandom), coitus interrupts and natural family planning; less used
methods may be of the surgical hazard associated are, female
sterilization and vasectomy [1,4].
Combined hormonal contraceptives (COCs) are one of the
most popular methods of birth control, worldwide. This reliable
form of contraception may have several contraindications to use.
In fact COCs could induce adverse effects, most of them not serious
but some which can be life threatening.
Abnormal uterine bleeding is a common side effect of all forms
of hormonal contraception. Combined oral contraceptives are
classified by the International Agency for Research on Cancer as a
cause of cervical cancer [3,7].
Progesterone-only contraception avoids the risks and side
effects of estrogen. All Progesterone-only methods work by a local
effect on cervical mucus by inducing proliferative effects in the
epithelial cells and on the endometrium, by making it thin and
atrophic, thereby preventing implantation and sperm transport
Progesterone only pill (POP) is taken every day without a
break. It is ideal for women at times of lower fertility. If the POP
fails, there is a slightly higher risk of ectopic pregnancy. POPS have
many side effects including Changes in bleeding patterns in forms
of frequent bleeding, Irregular bleeding, Infrequent bleeding and
Prolonged bleeding beside it is reported to cause headaches,
dizziness, mood changes, breast tenderness and abdominal
pain. At biochemical level progesterone is known to oxidize LDL
with subsequent arterial injury [1,7]. Two injectable forms of
progesterone are widely distributed depo-provera (150mg) and
norethisterone enanthate (200mg)  (Figures 1&2).
Most women choose depo-provera and each injection lasts for
12 weeks with a 2-week grace period, norethisterone enanthate
only lasts for 8 weeks and is not nearly so widely used. Depo-
Provera is highly effective and causes low estrogen levels and
this is associated with loss of bone mineral density. Bone density
seems to recover when Depo-Provera is stopped. Women with preexisting
risk factors for osteoporosis should probably be advised
not to use Depo-Provera in the long term. Particular side effects
of Depo-Provera include: weight gain, delay in return of fertility,
persistently irregular periods [1,3,5].
Implanon consists of a single (silastic rod) that is inserted
subdermally under local anaesthetic into the upper arm. It
releases the progestogen etonogestrel 25-70mg daily (the dose
released decreases with time), which is metabolized to the thirdgeneration
progestogen desgestrel. It lasts for three years and
thereafter can be easily removed and a further implant inserted
if requested .
The aim of this review is to detect early changes in cervical
cytological smears and to correlate these finding to the possibility
of developing serious conditions that could be prevented.
Persistent consumption of hormonal contraception especially for
long duration of time might lead to serious cervical abnormalities
in form of dysplastic changes or even cervical carcinoma. Many
factors might contribute to presence or absence of cervical
abnormalities such as duration of consumption of hormonal
contraception, age, work and the type of hormonal contraception
used. Worldwide it is estimated that more than 200 millions of
women using different forms of hormonal contraception . Thus,
the ultimate goal of this review is to detect early minor changes
that occur in cervical mucosa in relation to the use of hormonal
contraception, it is an attempt to avoid the serious complications
that may follow; i.e. cervical intraepithelial neoplasia (CIN) or even
an invasive carcinoma which might be at the expense of time and
money and may lead to unfortunate death which could be avoided.
Cervical intra epithelial neoplasia (CIN) also known as
dysplasia, is defined as a spectrum of intraepithelial changes that
begin as well differentiated intra epithelial neoplasm and classified
as a mild dysplasia, and ends with invasive cancer . The
neoplastic changes are confined to the squamous epithelium and
include nuclear pleomomphism (abnormal chromatin aggregates),
loss of polarity with increase in the nuclear/cytoplasmic ratio and
the presence of abnormal mitoses (mitotic figures) .
CINCIN is graded from 1-3; the grading is based on the amount
of undifferentiated cells present from the basement membrane
to the surface epithelium. When up to one-third of this distance
is involved the grade is CIN1, when more than one-third and up
to two-thirds is involved the grade is CIN2, and when more than
two-thirds are involved the grade is CIN3. When the patient has
full thickness involvement from the basement membrane to the
surface epithelium, this condition is referred to as carcinoma in
situ (CIS). Although the current thory is that CIS is part of the
spectrum of CIN. While the presence of CIN 3 implies a greater risk
for the development of invasive cancer than does the presence of
CIN 1 or 2, it is only a relative risk. There are currently no objective
markers of increased risk for invasion. These are desperately
needed in order to plan interventions and assess their impact [8,9]
It is an invasive carcinoma that arises from the cervical
epithelium. Most commonly seen in middle aged women (average
age is 40-50 years). This condition presents mainly as vaginal
bleeding, especially post-coital, or cervical discharge. Risk factors
include; HPV infection, immunodeficiency status, smoking and
OCP which considered as a cause of early cytological abnormalities
of cervical exfoliated cells. The most common subtypes of cervical
cancer are squamous cell carcinoma (80%) and adenocarcinoma
(15%). Advanced tumors often invade through the anterior
uterine wall into the urinary bladder, blocking the ureters.
Hydronephrosis with postrenal failure is a common cause of death
in advanced cervical carcinoma [2,10].
A study done by Brinton L, Reeves WC et al, in Entebbe, Uganda,
in September 2013 ; concluded that the recent long terms users
of (COC) at high risk of developing invasive cervical carcinoma
with RR=1.7 . An article done by R. Sabatini1, R. Cagiano et al,
stated that current users of combined oral contraceptives have an
increased risk for cancer of the cervix, breast, and liver compared
with non-users, while it was generally reported that current users
of combined oral contraceptives have a reduced risk of cancer of
the endometrium, ovaries, and possibly, colorectum. Also, they
stated that cervical cytological studies reported the significantly
high frequency of squamous intraepithelial lesions (SILs) in the
early stages of contraception with Norplant insertion, but after 1
year a progressive decline of them was found and after 3 years no
SIL was seen .
Combined oral contraceptives are classified by the
International Agency for Research on Cancer as a cause of cervical
cancer . A study done by Appleby P, Beral V, et al as part of
the international collaboration of epidemiological studies of
cervical cancer in 2007, stated that among current users of oral
contraceptives the risk of invasive cervical cancer increased with
increasing duration of use (relative risk=RR for 5 or more years’
use versus never use, 1.90) .
A prospective cohort study- done by Beral V, Hannaford, et
al, in the Royal college of general practioners’-of 47000 women
followed since 1968, which stated that, those who used OCP had
a significant higher incidence rate of cervical cancer than neverusers
and the standardized incidence rate for cervical cancer in
women who had taken the pill for more than 10 years was 4 times
that in never-users .
A study done by Diaz J, et al.  in Brazil concluded that
bleeding side effects is a major reason for discontinuation. In
this study, discontinuation was more closely related to increased
or decreased bleeding than to irregular, unpredictable bleeding.
At biochemical level progesterone is known to oxidize LDL with
subsequent arterial injury .
Mahgoub et al.  found that Usage of hormonal contraception
is linked to increase the possibility of developing dysplastic
changes in the cervical exfoliated cells which in turn harboring
the potentiality of developing cervical cancer. There is strong
association between the duration of hormonal contraception
usage and dysplastic changes in the cervical exfoliated cells.
a) Usage of hormonal contraception is linked to increase
the possibility of developing dysplasia which in turn harboring
the potentiality of developing cervical cancer.
b) There is strong correlation between the duration of
hormonal contraception usage and dysplastic changes on the
cervical exfoliated cells.
c) The Incidence density of dysplastic changes on the
cervical exfoliated cells among the exposed group was higher
than that of the not-exposed group.
d) Interpretation of the Risk Ratio concluded that, the
women who used hormonal contraception were 4 times more
likely to develop dysplastic cervical lesions in comparison
with those who did not use hormonal contraception.
a) Health education sessions should be conducted to the
medical personnel who dealing with hormonal contraception
regarding the potential side- effects of them.
b) Hormonal contraception should be prescribed by a trained
doctor or midwife after taking a detailed history from the user, and
a clear instruction about when to stop the hormonal contraception
should also be provided.