Bachelor Thesis

39 Pages·2011·1.49 MB·English

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Bachelor Thesis
Oral contraceptives and their impact on the
cardiovascular system

Medical University of Graz
Health and Nursing Sciences

Submitted by:
Tanja Wurm
0833070

Module ‘Pharmacology’
Supervised by:
Ao.Univ.Prof. Dr. Ulrike Holzer
Institute for Experimental and Clinical Pharmacology
Universitätsplatz 4
8010 Graz
Submission date:
April 2011
Ehrenwörtliche Erklärung
Ich erkläre ehrenwörtlich, dass ich die vorliegende Bachelorarbeit selbstständig und ohne
fremde Hilfe verfasst habe, andere als die angegebenen Quellen nicht verwendet habe
und die den benutzten Quellen wörtlich oder inhaltlich entnommenen Stellen als solche
kenntlich gemacht habe. Weiters erkläre ich, dass ich diese Arbeit in gleicher oder
ähnlicher Form noch keiner anderen Prüfungsbehörde vorgelegt habe.

Graz, am 5.April

I
Table of contents
1 Introduction 1
1.1 Motivation for the topic 1
1.2 Major aims 1
1.3 Research questions 2
2 Methods - Search strategies 2
3 Part I: The female reproductive system 3
3.1 The physiology and function of the ovary 3
3.2 The menstrual cycle and the endocrine control 3
3.2.1 The menstrual cycle 4
3.2.2 Hormones involved in the female cycle 4
4 Part II: Oral contraceptives 5
4.1 The different types of oral contraceptives 6
4.1.1 Combination/combined oral contraceptives 6
4.1.2 Progestin-only contraceptives 7
4.2 Classification of oral contraceptives according to their estrogen content 7
4.3 Overview of agents available in Austria 8
4.4 The chemical structure of combined oral contraceptives 11
4.4.1 Meliane® as an example for monophasic oral contraceptives 11
4.4.2 Qlaira® as an example for tetraphasic preparations 12
4.5 Mechanism of action 13
4.5.1 Mechanism of action – Combination oral contraceptives 13
4.5.2 Mechanism of action – Progestin-only contraceptives 14
II
4.6 Using oral contraceptives correctly 14
4.7 Contraindications to oral contraceptive use 14
5 Part III: Oral contraceptives and their impact on the female body
focusing on cardiovascular side effects 16
5.1 Oral contraceptives and their side effects – an Introduction 16
5.1.1 Known side effects of combined oral contraceptives 16
5.1.1.1 Cardiovascular side effects and risks 16
5.1.1.1.1 The risk of venous thrombosis and thromboembolism 17
5.1.1.1.2 Up-to-date information on the topic 18
5.1.1.1.3 The increased risk of thromboembolism in 3rd generation oral
contraceptives 19
5.1.1.1.4 The risk of hypertension 21
5.1.1.1.5 Arrhythmogenesis 21
5.1.1.1.6 Overview of the mechanism of estrogen and progestin action
causing cardiovascular disease 22
5.1.1.1.7 The risk of myocardial infarction 23
5.1.1.1.8 Stroke 24
5.1.1.2 Cancer 25
5.1.1.2.1 Cervical cancer 25
5.1.1.2.2 Liver cancer 25
5.1.1.2.3 Breast cancer 25
5.1.1.3 Effects on serum lipid levels 26
5.1.2 Known side effects of progestin-only oral contraceptives 26
5.2 Benefits of combined oral contraceptives 27
III
6 Conclusion 28
6.1 Findings to the first research question 28
6.2 Findings to the second research question 29
7 Discussion 30

IV
Abstract
Aim: The major aim of this bachelor thesis is to answer two questions. The first question
should give an overview of the different types of oral contraceptives, their chemical
compounds and their mechanism of action. The second question should give an overview
of the side effects detailing cardiovascular effects.
Methods: A literature search was done at the library of the Medical University of Graz and
through the databases of PubMed, Cinahl, Cochrane Library and ISI Web of Knowledge.
Results: Oral contraceptives consist basically of synthetic estrogens and progestins. They
act by preventing ovulation and by thickening the cervical mucus.
The cardiovascular side effects are hypertension, myocardial infarction, stroke, venous
thrombosis and venous thromboembolism. Oral contraceptives can also have an impact
on serum lipid levels and there can also be effects on the development of cancer.
Conclusion: There are many aspects which have to be considered before judging the
possible side effects of oral contraceptive use.
Zusammenfassung
Ziel: Das Ziel dieser Arbeit ist es zwei Fragen zu beantworten. Die erste Frage beinhaltet
die verschiedenen Arten oraler Kontrazeptiva, ihre chemische Zusammensetzung und den
Wirkmechanismus. Die zweite Frage soll die wesentlichen Nebenwirkungen unter
besonderer Berücksichtigung der kardiovaskulären Auswirkungen abdecken.
Methode: Es wurde eine Literaturrecherche in der Bibliothek der Medizinischen Universität
Graz durchgeführt. Außerdem wurden die Datenbanken PubMed, Cinahl, Cochrane
Library und ISI Web of Knowledge durchsucht.
Ergebnis: Orale Kontrazeptiva bestehen grundsätzlich aus synthetischem Östrogen und
einem Gestagen. Durch sie wird die Ovulation gehemmt und die Zervixschleimhaut wird
dicker. Die kardiovaskulären Nebenwirkungen sind Hypertension, Myokardinfarkt,
Schlaganfall, venöse Thrombose und Thromboembolie.
Zusammenfassung: Bei der Beurteilung der möglichen Nebenwirkungen von oralen
Kontrazeptiva gilt es viele Aspekte zu berücksichtigen.
V
1 Introduction

1.1 Motivation for the topic
There were lots of reasons for me to write my Bachelor thesis on this topic. During my
degree program in Health and Nursing Sciences it is necessary to write two bachelor
theses. Therefore I looked for special topics in which I was interested the most. The
module pharmacology was very interesting for me and that‟s why I decided to write my
bachelor thesis on a specific topic dealing with pharmacology.
I think that nearly all women are concerned with contraception. In my opinion it is not
always easy to find the optimal method. I also think that many women do not know enough
about the topic. There are loads of information on the World Wide Web and guidebooks
but they do not always tell the truth.
In my Bachelor thesis I want to focus on oral contraceptives. I cannot talk about all the
different forms of contraception, because there is not enough space for it. For me it is
important to give information on the different compounds of different preparations and to
show the possible side effects on the female body.

1.2 Major aims
There are several objectives which I want to reach through this bachelor thesis. I want to
give a short introduction in which I would like to explain the female reproductive system. It
should include some basic knowledge about the female body to understand the
mechanism of action of oral contraceptives.
Afterwards I want to describe the chemical compounds of the different forms of oral
contraceptives and then I want to come up with an overview of all side effects detailing
cardiovascular effects. To complete the topic I will finally deal with the benefits of oral
contraceptives.

1
1.3 Research questions
The bachelor thesis should basically answer two questions:
1. Which compounds do oral contraceptives consist of and how do they work?
2. What are risks and benefits of oral contraceptive use?

2 Methods - search strategies
The thesis is designed as a literature review on side effects of oral contraceptives with
particular emphasis on the cardiovascular effects. Before I could start writing I searched for
literature available at the library of the Medical University of Graz. For the basics which
should introduce the topic I found two books providing the basis of pharmacology. The first
I chose was called Goodman and Gillman‟s „The pharmacological basis of therapeutics‟.
The second book was called „Integrated Pharmacology‟ by Page et al. (2006). To provide
information on the different oral contraceptives I used the „Austria Codex‟. The main
reason for that is that there are different trade names for the agents all over the world and I
wanted to use the names of those which are sold in Austria.
I also looked for research articles in different data-bases such as PubMed, Cinahl and
Cochrane Library. The most important search terms I used were: „Oral contraceptives‟,
„oral contraceptives AND effects‟, „oral contraceptives AND venous thrombosis‟, „pill AND
lipid metabolism‟. After the queries there was a lot of material which I had to read and I
tried to find those research papers which answered my research questions best.
For the chemical structure of the preparations I used the database PubChem.
The information on the cardiovascular effects and lipid metabolism are based on research
articles found on PubMed, Cinahl and Cochrane Library.

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3 Part I: The female reproductive system
Before going into detail with oral contraceptives and their mechanism of action it is of great
importance to understand the basics of the female cycle. As oral contraceptives interfere
with the female cycle it is crucial to know a little about it.
“The female reproductive tract consists basically of two ovaries which are surrounded by
the fallopian tube which joins the uterus. The uterus is a short muscular organ. The lower
end of the uterus narrows to form the cervix, which is a sort of muscle that contains a lot of
secretory glands. It protrudes into the vagina. The function of the cervix is to act as a
barrier to infection between the vagina and the uterus (Page et al. 2006 p.340).”

3.1 The physiology and function of the ovary
The ovary consists of follicles within a stroma which is surrounded by a membrane. Each
follicle contains a gamete, also called oocyte, ovum or egg.
The most important hormones from the ovary are the sex steroids estrogen and
progesterone.
The ovary provides the gametes for fertilization. It synthesizes hormones for the
reproductive tissues. The ovary also maintains the secondary female sex characteristics,
such as the enlargement of the breasts or the widening of the hips (Page et al. 2006,
p.339).

3.2 The menstrual cycle and the endocrine control
At the beginning the menstrual cycle will be explained in order to enable a better
understanding of the female reproductive tract. Afterwards a short information will be given
about the hormones involved in the cycle.

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3.2.1 The menstrual cycle
The menstrual cycle is the period between two ovulations. It lasts between 24-32 days.
Day 1 of menstruation starts with shedding of the uterine endometrium. This takes about 3-
5 days.
Afterwards there is the so called proliferative phase of the cycle which lasts roughly until
day 14. In this phase, which is also called the follicular phase, the developing follicles
produce estradiol. Estradiol causes the uterine endometrium to proliferate. Ovulation
usually occurs on the 14th day.
The proliferative phase is followed by the luteal or secretory phase, which lasts 14 days.
During the luteal phase the ruptured follicle becomes a so-called corpus luteum that
produces progesterone which is the reason why the endometrium becomes secretory
(Page et al. 2006, p.339).

3.2.2 Hormones involved in the female cycle
The endocrine control of the ovary is operated by hormones. The production of the basic
female hormones estrogen and progesterone is controlled by the HPA (hypothalamic-
pituitary-ovarian axis). This involves the production of GnRH (gonadotropin-releasing
hormone) which influences the production of LH (luteinizing hormone) and FSH (follicle-
stimulating hormone). LH increases the production of androstenedione and testosterone.
FSH induces the aromatization of the androgens to estrogens (Page et al. 2006, pp.339-
340).
“Endogenous estrogen is produced by the ovaries in the form of 17β-estradiol, which acts
at two estrogen receptors, ERα and ERβ, with equal binding affinity.
Endogenous progesterone blood levels rise each month from the corpus luteum after
ovulation and remain high during the luteal menstrual phase to inhibit ovulation, and
eventually drop at the time of menstruation (Shufelt & Bairey Merz 2009, p.2).”

Figure 1 below shows the female cycle as it has been explained above. The figure should
provide help to understand the very complicated processes during the cycle.
Due to lack of space, however, these will not be described in detail.
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