Adverse effect of combined oral contraceptive pills

Abstract

Oral contraceptive pills contain estrogen and progestin that are synthetic analogs of natural hormones. These synthetic hormones affect the hypothalamus-pituitary-gonadal axis of the female reproductive system. There are many types of contraceptives; most of the oral contraceptive pills prevent pregnancy by inhibiting ovulation. Estrogen and progestin are two female reproductive hormones that are critical. Typically, estradiol is produced by growing follicle (ovaries) which stimulate the hypothalamus to produce gonadotropin-releasing hormone (GnRH), which further stimulate the anterior pituitary to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH production triggers the ovulation. Similarly, the progesterone is produced by corpus luteum (ovaries), which triggers the production of FSH and LH. There are many types of progesterone available. Long term usage of synthetic estrogen and progesterone can disturb the balance between the level of these hormones in the body. This imbalance may lead to severe side effects like breast cancer, cervical cancer, thrombosis, direct impact on the brain, and infertility.

Keywords: Estrogen, Progesterone, Contraceptives, Herbal Contraceptives

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Online - 2455-3891
Print - 0974-2441Vol 10, Issue 1, 2017
ADVERSE EFFECT OF COMBINED ORAL CONTRACEPTIVE PILLS
AKSHARA SHUKLA1, ROHITASH JAMWAL2, KUMUD BALA1*
1Amity Institute of Biotechnology, Amity University, Uttar Pradesh, Sector-125, Noida, India. 2Department of Biomedical and
Pharmaceutical Sciences, University of Rhode Island, Kingston, USA. Email: kbala@amity.edu
Received: 09 August 2016, Revised and Accepted: 20 September 2016
ABSTRACT
Oral contraceptive (OC) pills contain estrogen and progestin that are synthetic analogs of natural hormones. These synthetic hormones affect
the hypothalamus-pituitary-gonadal axis of the female reproductive system. There are many types of contraceptives; most of the OC pills prevent
pregnancy by inhibiting ovulation. Estrogen and progestin are two female reproductive hormones that are critical. Typically, estradiol is produced
by growing follicle (ovaries) which stimulates the hypothalamus to produce the gonadotropin-releasing hormone, which further stimulates the
anterior pituitary to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH production triggers the ovulation. Similarly, the
progesterone is produced by corpus luteum (ovaries), which triggers the production of FSH and LH. There are many types of progesterone available.
Long-term usage of synthetic estrogen and progesterone can disturb the balance between the level of these hormones in the body. This imbalance may
lead to severe side effects such as breast cancer, cervical cancer, thrombosis, direct impact on the brain, and infertility.
Keywords: Estrogen, Progesterone, Contraceptives, Herbal contraceptives.
INTRODUCTION
Contraception is a method to prevent unwanted pregnancy. Combined
oral contraceptives (COCs) have become a popular method of birth
control due to their contraceptive efficacy and good tolerability
profile [1]. These pills contain hormones that act on the reproductive
system of female leading to contraceptives such as estrogen and
progesterone. OCs are the combination of estrogen and progestin or
only progestin. Over the years, OCs have developed through gradually
reducing the dose of ethinylestradiol (EE) and introducing 17-β
estradiol, and various generations of progestin [2]. There are manytypes
of estrogen and progesterone being used in pills like mestranol is a class
of estrogen, and the 3-methyl ether of EE and norethynodrel is a type
of progestin; its dose was 9.85 mg per pill initially. In clinical studies,
the efficiency of contraceptive was excellent, but this drug caused
many side effects such as nausea, dizziness, headaches, stomachaches,
and vomiting; these are the symptoms that had presented by the 17%
women undergoing the clinical studies. Though, the death of a female
had been reported who was taking the contraceptive pills in 1961.
Although after so many years, OCs have developed by reducing the
dose of estrogen and by discovering a new generation of progestins,
and other routes of COC administration have been developed [3]. The
findings of the previous research show some severe side effects of these
pills. Thus, this short study is focused on the overview of the female
reproductive system and its regulation, hormonal contraceptive pills,
mechanism of action of these drugs, and side effects of OC pills.
OVERVIEW OF FEMALE REPRODUCTIVE CYCLE
The balance between estrogen and progesterone handles the
development and maintenance of the female reproductive system. Cellular
differentiation is regulated by progesterone while estrogen controls cell
proliferation. Thus, uterine endometrium has 3 phases (Fig.1)
1. The follicular phase (estrogen dominant) is a growth phase where
uterine glands grow and proliferate
2. During secretory (luteal) phase, (progesterone dominant) glands get
tightly coiled, and secrete
3. During menses, spiral arteries constrict, and endometrium sloughs.
REGULATION OF REPRODUCTIVE HORMONES IN FEMALE
The hypothalamus is responsible for the secretion of gonadotropin-
releasing hormones (GnRH), which then stimulates the anterior
pituitary to release follicle-stimulating hormones (FSH) and luteinizing
hormones (LHs). FSH stimulates follicle growth, maturation of ovum
leading to the release of estradiol from follicles. High levels of estradiol
for a sufficient period stimulate sudden secretion of LHRH (GnRH-
positive feedback), which induces a surge of LH (and FSH) secretes
from the anterior pituitary (Fig. 2). LH surge leads to ovulation and
assists the development of corpus luteum. Corpus luteum then releases
progesterone. Increased levels of estrogen and progesterone will
signal anterior pituitary and hypothalamus to stop the secretion of
FSH and LH. The resulting negative feedback leads to deterioration of
corpus luteum, which further decreases the amount of estrogen and
progesterone [5].
The contraceptive pills work on the same hormonal axis mentioned
above. These drugs modulate the normal condition of this hormonal
regulation, which delays the follicle development in females. There are
different categories of hormonal contraceptives and different mode of
administration. Although, this study is focused only on COC pills and
progesterone-only pills.
CATEGORY OF HORMONAL CONTRACEPTIVES PILLS
Previously, administration of COCs used to deliver a dose of high
EE or mestranol along with progestin, resulting in increased risk of
cardiovascular disease. However, the therapeutic combinations of COC
have substantially changed over the past few decades (Fig. 3). Current
COCs contain a low dose of EE or estradiol (E2) combined with new
progestins, and many alternatives or nonoral routes of administration
have been evolved. Besides, progestin-only contraceptive pills are a
contraceptive method that may be the better option for women with
several routes of administration are available these days [6].
ORAL ROUTE OF ADMINISTRATION
OCs can be categorized into two main categories:
• COC pills and
• Progestin-only pills (POPs).
COCS PILLS
Synthetic estrogen (with high dose) and androgenic progestin like
norethisterone acetate or norethindrone had been marketed as the first
COC. The present COCs deliver low doses of EE every day. E2 valerate
© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2017.v10i1.14565
Review Article

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Shukla et al.
and dienogest have been newly approved in Europe and the USA as
quadriphase OC. Another monophasic COC that combines E2 with
nomegestrol acetate, a progesterone-derived progestin, is now being
marketed in several countries in Europe [7-9].
Estrogen in COC
The dose of estrogen has been decreased by drug companies to reduce
the risk of cardiovascular disorders. The estrogen component, EE or
17α estradiol is used in COCs available these days (Table 1). Over the
years, the dose of EE has reduced from 50 to 30-35 mg and gradually
to 20-15 mg. Pills are now segregated into higher and lower than
30 mg dose of EE. This reduction has been made feasible due to the
accessibility of new classes of progestin. In the 1970s, the concept
arose to use the natural 17β estradiol in COCs, although no satisfactory
formulations were available for years. In few cases, the pills containing
17β-E2 were contraceptive, but females showed low tolerance
experiencing excessive bleedings. There are two combinations have
been commercialized containing estradiol (E2). Selective estrogen
receptor modulators are under development, which has estrogenic
activity on bone and endometrium but antiestrogenic activity on the
breast, e.g., estetrol [3].
Progestins in COC
In the different combined pills available nowadays, the progestin
component in the pill inhibits LH peak, decreases ovarian sensitivity
to FSH, and therefore, decreases estradiol production. The estrogenic
component regulates endometrium proliferation and compensates
estrogenic deficiency induced by the antigonadotropic effect of
the progestin. Progestins are classically characterized according to
their structural origins. They bind to progesterone receptors, but
progestins may also bind to other steroid receptors such as androgen,
glucocorticoid, and mineralocorticoid receptors. Most of the progestins
contained in COCs were initially derived from testosterone and are
called 19-nortestosterone derivatives. Norethisterone is an estrone,
and norethisterone acetate and norethynodrel are gonanes. Few pills
containing first-generation progestins are still available. Their side
effects such as acne, oily skin, and decreased high-density lipoprotein,
mainly due to their androgenic properties, are the primary cause for
their progressive withdrawal. Over the years, progestins with less
androgenic effects have been developed (Table 2). Levonorgestrel
(LNG) and norgestrel are second-generation progestins. Third-
generation progestin includes desogestrel (DSG), with its active
metabolite 3-keto-DSG (also named etonogestrel), norgestimate (and
its active 17-deacetylated metabolite, norelgestromin [NGMN]), and
gestodene (GSD) [3].
Different progestins used in COCs are derived from progesterone.
Molecules such as chlormadinone acetate, cyproterone acetate (CPA),
and medroxyprogesterone acetate are called pregnane derivatives, as
they are derived from 17-OH progesterone [10]. Some newer progestins
have been available more recently in OCs such as drospirenone (DRSP).
This progestin possesses antimineralocorticoid and weak androgen
proprieties. Dienogest is a hybrid progestin, derived from the estrane
group but does not exert the androgenic effects of the testosterone
derivatives. A Cochrane review evaluated the effectiveness and side
effects of different progestogens [11]. In this comparative study,
13,923 participants were included in a total of 30 trials enabling
16 comparisons. The conclusion of this Cochrane Review mentions
that women using COCs containing second-generation progestogens
may be less likely to discontinue than those using COCs containing
first-generation progestogens. Based on one small double-blind trial,
third-generation progestogens may be preferable to second-generation
preparations concerning bleeding patterns, but further evidence is
needed [3].
Millions of women have used estrogen and progestins as effective
COCs. OCs modify surrogate markers such as lipoproteins, insulin
response to glucose, and coagulation factors that have been associated
with cardiovascular and venous risk. EE exerts a stronger effect that
natural estradiol (E2) on hepatic metabolism. New progestins with high
specificity have been designed to avoid interaction with other receptors
and prevent androgenic, estrogenic, or glucocorticoid-related side
effects. The risks and benefits of new progestins used in contraception
depend on their molecular structure, the type and dose of associated
estrogen, and the delivery route [3].
Progestin-only contraceptive pills (POPs)
POPs delivers a very low concentration of progestin every day
(norethindrone, LNG, or DSG). While the developments of OCs pills are
based on progestin-only components, recently POPs are less widely
used than COC as a result of their negative uterine tolerance [12].
Though, POPs may be an attractive contraceptive choice for women
with contraindications to COCs (Table 3).
ALTERNATIVE (NONORAL) MODE OF ADMINISTRATION
These types of contraceptives provide steady supplies of hormones.
They can be delivered in a combination of estrogen and progestin or
progestin only.
Combined contraceptives
There are two types of other (non-oral) mode of administration
available: Patch and vaginal ring. The patch (transdermal) consists of
EE along with NGMN and the vaginal ring consists of EE along with
etonogestrel.
Progestin-only contraceptive
Currently, there are three major routes of nonoral administration of
contraceptives which are frequently used in the USA and Europe [3].
Many synthetic hormonal contraceptives are available with different
brand names, but these all contain synthetic estrogen and progesterone
and having severe side effects. The details of few synthetic contraceptive
drugs are mentioned in Table 4.
ADVERSE EFFECT OF SYNTHETIC CONTRACEPTIVE PILLS
It has been reported that OC pills may cause many side effects in a long
run, and authors have discussed a few of those side effects in this article.
Table 1: Two type of combinations of estradiol [3]
Active ingredients Classification of components
Quadriphasic COC-E2
valerate+dienogest
E2 valerate-synthetic estrogen,
metabolized into 17 bE2
Monophasic COC-17b
E2+nomegestrol acetate
Nomegestrol acetate-progestin
COC: Combined oral contraceptive
Table 2: Different generations of progestin used in COCs [3]
1stgeneration
progestin
2nd generation
progestin
3rd generation
progestin
Norethisterone acetate Norgestrel NGM
Lynestrenol LNG DSG
Ethynodiol acetate GSD
Norethynodrel
COCs: Combined oral contraceptives, NGM: Norgestimate, DSG: Desogestrel,
GSD: Gestodene, LNG: Levonorgestrel
Table 3: Mode of administration of progestin [3]
Mode of administration Time duration
Injectable (intramuscular-medroxyprogesterone) 3 months
Single rod implant (LNG/etonogestrel) 3 years
Intrauterine device (low dose of LNG) 3-5 years
LNG: Levonorgestrel

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Effects on brain structure
Adult brain structure is subject to dynamic changes with age. These
changes differentially affect brain areas, such as gray matter volumes
in some regions, decline more strongly with age than others. An age-
related strong decline has been demonstrated in the prefrontal cortex,
as well as the hippocampus. Recent results showed that regional gray
matter volumes in the prefrontal cortex, as well as the cingulate anterior
gyrus, are larger in mixed samples of androgenic and antiandrogenic
OC users compared to nonusers [22]. These regions are already larger
in women when compared to men. However, regional gray matter
volumes of OC users were also greater in the cerebellum, hippocampi,
parahippocampus, and fusiform gyri [23]. Those regions are on the
average larger in men compared to women. Results from rodent
hippocampi suggest that these volume increase may be attributed to an
increase in synaptic spin density mediated by estrogen receptors [24],
but an increase in astrocyte volume in response to estradiol has also
been suggested [13].
Hormonal contraceptives and risk of venous thromboembolism
(VTE)
It has been reported that VTE risk is related to COC [25]. The risk of VTE is
higher during the 1st year of use depending on the different combinations
of COCs. Recently, new formulations of OCs and nonoral routes of
administration have been evaluated in the context of VTE risk [26-28].
Based on the epidemiological findings, the risk of VTE is higher among
those using 30-35 mg of within different types of progestin as compared
to COC containing LNG [28]. With the same doses of EE (30-35 mg), the
COC-containing DRSP, EE CPA, DSG, or GSD also increased the risk of VTE
as compared to COC-containing LNG. It has also been reported that use of
nonoral routes of combined contraceptives, patch, or vaginal ring is also
associated with a higher VTE risk compared with the second-generation
pills [28]. The changes found to be more deleterious to users of this new
progestin than among LNG users. In combination with EE, these new
progestin appears to induce resistance to activated protein C (APC),
which is a surrogate marker of VTE risks. The effect on APC resistance of
Table 4: List of synthetic hormonal contraceptive pills available, their mode of action and their side effect
Name Active component Mode of action Side effects References
Estradiol
valerate
Estradiol valerate 2 mg Estrogens diffuse into their target cells
(i.e., cells in the female reproductive tract,
mammary glands, hypothalamus, and
pituitary) and bind to receptor proteins
Abnormal hair growth,
Breast tenderness, changes
in sex drive, cramps,
dizziness, hair loss, headache,
lightheadedness
[13]
Femilon DSG BP 0.15 mg
Ethinylestradiol IP 0.02 mg
Once bound to the receptor, progestins like
DSG will slow the frequency of GnRH from the
hypothalamus and blunt the pre-ovulatory LH
surge
Femilon contraceptive pill unleashes ethinyl
estradiol and DSG into the blood stream
Vaginal infections, urinary
tract infections, Breast pains
and engorgement, auditory
disturbances
[14]
CPA and
ethinylestradiol
CPA 2 mg ethinylestradiol
0.035 mg
Binds to the progesterone and estrogen
receptors slowers the release of GnRH from
the hypothalamus and blunt the pre-ovulatory
LH surge
blood clots cancers such as
breast or cervical cancer
[15]
Estrogen and
progestin
GSD BP 60 mcg
ethinylestradiol 15 mcg
Estrogens increase the hepatic synthesis
of SHBG and other serum proteins and
suppress FSH from the anterior pituitary. The
combination of an estrogen with a progestin
suppresses the hypothalamic-pituitary system,
decreasing the secretion of GnRH
Severe chest pain and cough of
acute onset, severe headache,
vision problems, dizziness
[16]
DSG and
ethinylestradiol
tablets
DSG 0.15 mg
ethinylestradiol 0.03 mg
Binds the estrogen and progesterone receptor,
inhibits ovulation
Severe allergic reactions,
bloody diarrhea, breast lumps
pain or discharge fainting,
frequent or painful urination
migraines, missed menstrual
period
[17]
Ovipauz
levonorgestrel
Levonorgestrel IP 0.15 mg
ethinylestradiol 0.03 mg
It inhibits ovulation, prevents transport of
sperm or eggs and thus prevents fertilization
and alters the lining of the uterus to prevent
Ovipauz-levonorgestrel
may cause thrombotic and
thromboembolic disorders,
vascular problems, hepatic
neoplasia, carcinoma of
breasts and reproductive
organs, gallbladder disease,
ocular lesions
[18]
Crisanta LS Ethinyl estradiol 0.02 mg
DRSP 3 mg
Progestins such as DRSP diffuse freely into
target cells in the female reproductive tract
and bind to the progesterone receptor. And
block the GnRh release and LH surge
Darkening of facial skin,
allergy, mood swings
[19]
Duoluton
levonorgestrel
Levonorgestrel IP 0.25 mg
ethinylestradiol 0.05 mg
Levonorgestrel tricks the body processes into
thinking that ovulation has already occurred,
by maintaining high levels of the synthetic
progesterone. This prevents the release of
eggs from the ovaries
Local skin reaction,
depression, liver impairment,
reduce menstrual loss
[20]
Ovral G Norgestrel 0.5 mg
ethinylestradiol 0.05 mg
The combination of an estrogen with a
progestin suppresses the secretion of GnRH
Stomach cramping, Vomiting,
dizziness
[21]
DRSP: Drospirenone, CPA: Cyproterone acetate, DSG: Desogestrel, GSD: Gestodene, SHBG: Sex hormone binding globulin, GnRH: Gonadotropin-releasing hormone

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the different molecules of progestin associated with the same EE dose has
been clearly investigated. It has been found that acquired APC resistance
(measured as the effect of APC on thrombin generation) may be related to
the thrombotic effect of hormonal contraceptives. Sex hormone binding
globulin (SHBG), a carrier protein synthesized by the liver, has found to be
positively correlated with APC resistance among pill users. It is, therefore,
another useful pharmacological marker to predict the thrombotic venous
safety of a combined contraception indirectly. Hence, SHBG appears to be
higher among users of DSG, DRSP, and CPA containing pills as compared
to those using LNG pills [29-31].
CONCLUSION
Contraceptive pills mainly work by inhibiting or delaying ovulation and
up to some extent preventing fertilization and implantation. Several
clinical studies have shown that COCs works primarily on either
inhibiting or delaying ovulation. Millions of women in this reproductive
age (14-45 years) are taking these medicines to delay pregnancy.
Many of the women have experienced side effects after taking COCs
or POPs such as spotting, weight gain or weight loss, nausea, breast
tenderness, severe headache, depression, darkening skin, and vaginal
infection. There is sufficient evidence in humans that combined oral
estrogen-progesterone contraceptives are carcinogenic in nature. This
assumption has made by increased risk for cancer of breast, cervical,
and liver. However, experiments in animals have provided inadequate
evidence for the carcinogenicity of progesterone, LNG, norgestrel, or
progestin-derived contraceptive pills. These contraceptives act as LH
receptor (LHR) and progesterone hormone receptor (PGR) inhibitors
and thus in long-term usage interferes with the ovulation cycle which
results in premature ovulation or delayed ovulation. However, herbal
compounds have been found to work as partial inhibitors of LHR and
PGR, and at the moment, they are being removed from the system, the
ovulation cycle is retained. Collectively, there is a need to work for herbal
analogs of these contraceptives which can be effective as well as safe.
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