IT ALL STARTS WITH
AN EGG AND A SPERM:
NATURAL FERTILIZATION
How does human fertilization occur? At first sight, a simple question – you’ve known the answer for years.
Or you thought you did, because it’s not really as straightforward as that. A complicated biochemical and
anatomical background underlies the process of merging a female egg and a male sperm to form what
becomes a baby. An understanding of this background is especially vital for couples unable to conceive
but who can be helped medically.
THE FEMALE REPRODUCTIVE SYSTEM
egg
ovary
fingerlike
projections
fallopian tube
womb
vagina
1
1| A woman’s reproductive organs.
Frequently asked question
Does ovarian stimulation affect the store
of eggs resulting in early menopause?
Find the answer on p. 80.
THEORY
A normal human female is born with about 300,000 to 400,000
eggs (also known as egg cells or ova) stored in two ovaries. She will
produce no further eggs during her lifetime. On the contrary, a large
number of these eggs die through a process of natural wastage,
leaving about 100,000 to 200,000 by the time of puberty. The
number remaining decreases over time until none are left, usually
at the age of about fifty, which marks the onset of menopause.
The ovaries normally release one ripe egg every four weeks during
a woman’s fertile years. This is known as ovulation. Finger-like
projections at the top of one fallopian tube catch the egg. The
egg is ready for fertilization by a sperm (from the male) while it is
inside the fallopian tube.
Cilia (tiny hair-like projections) covering the inner wall of the
fallopian tube gently waft the egg down to the uterus (or womb).
Meanwhile, the lining of the uterus (the endometrium) has
thickened in preparation for the arrival of an embryo.
If the egg is not fertilized or the embryo fails to implant in the
uterus, the mucous lining rapidly breaks up and is shed via the
vagina. This process is known as menstruation (having a period).
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THE MALE REPRODUCTIVE SYSTEM
brains
GnRH
hypofyse
FSH LH
hypothalamus
penis
testosterone
Testosterone
testicle
2
bladder
seminal
vesicle
vas deferens
prostate
gland
urethra
epididymis
penis
testicle
3
2| The hormonal ‘cycle’ of a man.
3| A man’s reproductive organs.
THEORY
4| Testosterone Builder.
Men who take testosterone in order to increase
their muscle mass are giving an incorrect signal
to their brain, i.e. that sufficient male hormone
is present in the body. This leads to a halt in
gonadotrophin production. But gonadotrophins are
necessary for the production and maturation of
sperm cells. Or how taking testosterone can lead
to a significant reduction in sperm production and
hence to infertility.
14
Sperm (spermatozoa or sperm cells) are produced in tiny tubes
(tubules) inside the male’s testicles (testes). Sperm production
begins in puberty and continues for the rest of a man’s life.
Lesser known is the fact that sperm production and maturation is
controlled by the same hormones that regulate women’s menstrual
cycles: the gonadotrophins LH and FSH (see illustration 5 for the
abbreviations). Together they stimulate the male reproductive
organs (gonads) into the production and the ripening of sperm
cells.
Gonadotrophins are secreted by the hypofyse, a small gland
in the brain which is controlled by the hypothalamus. The
hypothalamus secretes at regular intervals a hormone called GnRH
or Gonadotrophin Releasing Hormone, in a set rhythm dictating
the release of FSH and LH. During the process of production and
ripening of sperm the reproductive organs subsequently start to
produce sex hormones. In the male, this is primarily testosterone.
This is the hormone which turns a boy into a man. Production of
this hormone begins at puberty, from
which point on it controls the sexual
function and libido of the man. Is is also
responsible for the maturation of sperm
cells. Production of testosterone peaks
around the age of 30-35, then gradually
begins to decline.
In the male ‘cycle’, testosterone levels are
4
monitored in the brain. If sufficient levels
are present, the secretion of GnRH slows down, resulting in a lower
level of gonadotrophins produced. Similarly, if testosterone levels
are low, e.g. because the testis are producing less, the brain gets
the message that more FSH and LH are needed. In response the
secretion of GnRH accelerates, causing more gonadotrophins to
be released.
The sperm cells’ itinerary
As said before sperm cells are produced in tubules inside the
testicles. The production itself is a complicated process of cell
division and cell differentiation which takes about three months
in total. But of course the process occurs in thousands of tubules
and at different stages constantly, so that there is always a supply
of mature sperm available.
After its production in the testicle, the sperm travels to the
epididymis, which consists of one long, tightly coiled tube. The
sperm remains here for about a week, during which it continues to
mature and become more motile.
The epididymis also serves as a reservoir. During an orgasm, sperm
cells are expelled from the epididymis and set out on their journey
to the outside world via the vas deferens. On their way out they are
mixed with a nutrient-rich plasma from the prostate and seminal
vesicles. They are then ejaculated trough the urethra in the penis.
A normally fertile man will ejaculate between 1.5 and 4 ml of
semen containing some 20 to 200 million sperm per ml. See the
World Health Organisation (WHO) overview for other standards
which ‘normal’ sperm must meet.
Semen reaching the vagina undergoes a drastic transformation
within less than half an hour, changing from thick and sticky to
thin and fluid. Large numbers of sperm simply flow out of the
vagina, while most of the rest cannot get past the mucous around
the cervix (neck of the womb). A few hundred sperm at most –
motile and well-formed sperm – succeed in entering the uterus
and climbing to reach one of the fallopian tubes. If a ripe egg is
waiting there, there is a chance it will be fertilized – in principle
by a single sperm.
Normal sperm according to WHO-norms
Semen
volume
2,0 ml or more
pH
7,2 – 7,8
Sperm
concentration
20 million/ml or more
total count
40 million or more
progressive motility (fast or
slow forward movement)
> 50%
or
fast progressive motility
> 25%
normal formation
> 30%
vitality
> 50% live
white blood cells
< 1 million/ml
brain
GnRH
pituitary gland
FSH LH
THE MENSTRUAL CYCLE
ovary
A normal menstrual cycle lasts four weeks, although this time may
vary greatly from one woman to another and one cycle to another.
A menstrual cycle begins with the ripening of an egg and ends in a
period (menstruation) or pregnancy.
oestrogen
From day one to ovulation
(follicular phase)
mucos
lining
progesterone
womb
5
GnRH (Gonadotrophins Releasing Hormone):
encourages the menstrual cycle.
FSH (Follicle Stimulating Hormone):
develops the follicles in the ovaries.
LH (Luteinising Hormone): encourages ovulation.
hCG (Humane Chorion Gonadotrophin) or
pregnancy hormone: supports the further
development of the embryo into a baby.
5| Hormones involved in the menstrual cycle and/or
the IVF-treatment.
THEORY
The menstrual cycle is triggered by a low level of oestrogens
(female hormones) in the blood. This causes the hypothalamus, a
neural control centre at the base of the brain, to secrete GnRH (see
illustration 5). GnRH stimulates the pituitary gland, the master
endocrine gland located below the hypothalamus, to produce
follicle stimulating hormone (FSH) and luteinising hormone (LH).
These two hormones directly stimulate the woman’s reproductive
organs (gonads) and are therefore called gonadotrophins. GnRH
causes them to be ‘released’: hence the name Gonadotrophins
Releasing Hormone.
FSH stimulates the development of several ovarian follicles, small
sacs in the ovaries filled with liquid and each containing an egg.
Oestrogens secreted by these follicles cause the endometrium to
thicken in preparation for the possible implantation of an embryo.
Oestrogen secretion by the follicles causes oestrogen levels to rise,
hypothalamus
15
sending a message to the brain to slow down the release of GnRH.
As a result FSH production is reduced too, which stops further
follicle development and causes all but one to die. Nevertheless
there is always one dominant follicle that survives by adapting to
the low FSH levels, and this follicle alone continues to grow.
Under the influence of FSH and LH the egg in the dominant follicle
ripens. When oestrogen levels are sufficiently high an LH surge
occurs (a sudden increase in the amount of LH released), causing
final maturation of the egg. The egg is now mature and ovulation
can take place. There are approximately 12 to 40 hours between
the LH surge and ovulation. The LH surge occurs around day 12 of
a 28-day cycle, with ovulation occuring at around day 14.
MENSTRUAL CYCLE
Maturation of the egg within the follicle
Ovulation
LH surge
Luteinising
hormone
Progesterone
FSH
Oestrogens
MEN STRUAL C YCLE
Endometrium
Days
4
8
12
16
Ovulation
20
24
DAY
28
6
1
14
28
fallopian tube
FOLLICU L AR PHASE
Maturation of the egg
in the follicle
LUTEAL PHA S E
Possible fertilization
followed by
possible implantation
OVU L ATION
follicle
egg
PR EG NANT
OR
M E N STRUATION
7
From ovulation to day 28
(luteal phase)
After ovulation, the ripe egg travels through the fallopian tube to
the womb. The remaining empty follicle in the ovary turns into
a yellow glandular mass of tissue (corpus luteum). This does not
only secrete oestrogens (as the follicle did) but also progesterone.
Together these hormones stimulate the endometrium to thicken as
well as suppressing the production of FSH and LH by the pituitary
gland.
ovulation
Pregnancy
yellow mass of tissue
8
6| Hormonal changes during the
menstrual cycle.
7| Graphice representation of the
menstrual cycle. In practice, ovulation is
not that easy to predict.
THEORY
8| From follicle to yellow mass of tissue.
16
An egg may be fertilized up to about one day after ovulation.
A sperm retains its ability to fertilize an egg up to around two
days after ejaculation. Thus, a woman has three days of effective
fertility per cycle.
Fertilization takes place when the spermatozoa, having reached
the distal portion of one tube, succesfully penetrates into the egg,
this creating an embryo. The fresh embryo is then undergoing
successive divisions and is transported during a six day period
towards the uterine cavity. By then it has become a blastocyst
(multi-cellular germinal vesicle). It implants in the uterine mucosa
and starts to secrete hCG. This hormone can be identified in female
blood (or urine), which makes diagnosis of pregnancy possible.
During the first trimester hCG acts on the corpus luteum, which
then continues to produce oestrogens and progresterone. During
early pregnancy (first trimester) this hormonal cooperation sustains
embryo development.
This function is subsequently taken over by the placenta, an
organ which sees to the nutritive exchanges between mother and
foetus. By that time, the evolution of the pregnancy has become
autonomous.
Menstruation
If pregnancy does not occur, the corpus luteum will begin to break
down about ten days after ovulation. This causes the oestrogen and
progesterone levels to fall sharply, leading to the shedding of the
endometrium at around day 28 of the menstrual cycle. The woman
then menstruates, and the secretion of GnRH by the hypothalamus
and of FSH and LH by the pituitary gland begins all over again.
The first day of menstruation is also the first day of the new menstrual cycle. This
is why the timing of the IVF treatment is always counted from of the first day of
(red) bleeding (= day 1).
THEORY
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GIVING NATURE A HELPING HAND:
IN VITRO FERTILIZATION
If pregnancy through the usual method is not possible for you,
artificial insemination (see further, p. 53) or in vitro fertilization
(IVF) may be the solution.
REDUCED FERTILITY
weg van
de zaadcellen
9
10
9| The itinerary of the sperm cells through the male …
THEORY
10| … and thereafter through the female genital
organs.
18
Our knowledge of the human reproductive system and the
hormones which control it, teach us also what can go wrong:
• defective hormone production in the brain;
• defective hormone production in the reproductive organs;
• insufficient production of sperm cells;
• poor quality of sperm;
• problems related to the ripening process of egg cells;
• insufficient supply absence of eggs, poor quality of eggs;
• obstructions in the path of the sperm within the male
reproductive system;
• patency of the fallopian tubes;
• incorrect timing or location of the unity between sperm and
egg;
• implantation problems of the embryo.
We distinguish different causes of infertility:
• gynaecological causes: i.e. the woman’s fallopian tubes are
blocked or her uterus has certain malformations;
• hormonal indications: i.e. ovulation does not occur or is
disturbed;
• andrological indications: the man doesn’t produce (enough)
healthy sperm cells; and
• immunological indications: man or woman produce spermneutralising antibodies
Furthermore certain couples still aren’t expecting a child after
having regular sexual intercourse without any form of birth
control for a year or two, with the doctors failing to identify any
discernable cause. These cases are called idiopathic or unexplained
infertility.
12
11
THE TREATMENT IN A NUTSHELL
An IVF treatment is designed to help couples who suffer from
one or more of the aforementioned fertility problems. The natural
menstrual cycle will then be temporarily replaced by a medically
induced cycle.
Treatment begins with hormonal stimulation of the woman’s
ovaries. The aim is to produce several eggs in the course of one
menstrual cycle.
The ripe eggs are harvested (egg pick-up) from the ovaries just
before ovulation, using a very fine hollow needle. They are then
mixed in the laboratory with selected sperm provided by the man.
This may even be one single sperm cell, which is injected directly in
the egg. In this case we talk about ICSI.
If all goes well, some of the eggs will be fertilized and begin to
develop into embryos. One or two embryos are then transferred
to the woman’s uterus (embryo transfer), where we hope one will
implant itself and grow into a healthy baby.
In the past, two or three embryos used to be transferred, to increase
the chances of a successful implantation. However, the chances of
a multiple pregnancy (twins, triplets) are also increased. Improved
medical techniques often allow the transfer of only one embryo
nowadays, thus eliminating the chances of a multiple pregnancy,
and at the same time reducing the general health risks for woman
and child.
Any remaining good quality embryos are frozen and stored for
later use if the first attempt does not result in pregnancy or if the
woman wishes to have more children later. This avoids unnecessary
further stimulation of the ovaries and subsequent procedures.
Chances of a successful transfer are proportional to the number
of thawed embryos because they don’t all survive the thawing
process. Even if they are all of a good quality, the survival rate is
fifty percent on average. So it is perfectly possible that a couple
has embryos from a previous treatment, but still has to repeat the
entire IVF treatment for another attempt or for a second child.
13
14
11| Egg cumulus: the egg is in the top right-hand
corner surrounded by feeding cells.
12| Sperm under a microscope.
13| Eggs and semen are mixed in a glass dish
(classic IVF).
14| Insemination via ICSI: the sperm is sucked into a
needle and injected into the egg.
THEORY
19
Not easy but not painful either
In vitro fertilization is both a minor and a major treatment.
Physically, the demands are relatively small in that IVF involves a
series of minor, low-risk procedures, usually with little or no pain.
The drugs used may cause some short-term discomfort, but these
side-effects are not serious or lasting. Moreover IVF treatment is an
out-patient procedure and does not require you to stay overnight
in UZ Brussel.
However, IVF does make great mental demands on a couple. The
treatment involves many procedures and special routines and will
require a few (temporary) changes to your normal lifestyle. Of
course, you are certain to feel some stress, uncertainty and worry;
this is all quite natural and is focused on one crucial question:
will the treatment be successful? The effects of this will place a
heavy psychological burden on you, and you may find it extremely
wearing.
The CRG at UZ Brussel tries to give each couple every help and
guidance they may need. Helping you to satisfy your natural desire
for a child and ensuring your comfort during the treatment are
both very high on our list of priorities.
PREGNANCY IS NEVER A CERTAINTY
15
16
15| Fertilized egg, the day after IVF, still surrounded
by sperm.
THEORY
16| If everything goes well, the end result is
pregnancy.
20
The most important conclusion from practical experience is
that your individual chances of success are very difficult to
predict beforehand. Apart from the age of the woman the type
of treatment, the cause of the fertility problem, and chance play
a role. Sometimes the exact same treatment will produce results
after the second or third attempt. Why not the first time is not
always determinable. That is why counsellors nor doctors will
respond to questions about the chances of success of an individual
treatment. The risk to create unrealistic expectations – or on the
contrary erroneously stifle justified hope – is too great.
Based on our extensive experience for many years standing and
after examination of both partners we can of course give you a
general idea as to what the odds are. We’ll always try to assess your
medical chances as accurately as possible. On the whole we can
affirm that IVF/ICSI certainly is worth a try for many couples, but
that it doesn’t necessarily always results in the birth of a child.
Statistic chance of delivery
100 1
2
3
4
5
6
7
8
90
The average chance of success of
an IVF treatment is closely related
to the woman’s age, as can clearly
be seen in this graph.
80
70
Number of expected deliveries (out of 100 women)
60
50
20–29 age
40
30–34 age
35–37 age
30
average >
20–37 age
38–39 age
20
40–43 age
10
> 43 age
0
Number of fertilization cycles (IVF or ICSI)
This graph shows the relation between the expected percentage
of deliveries (not pregancies!), the woman’s age and the number
of IVF or ICSI attempts. The vertical axis shows how many women
(out of a hundred) of what age may give birth to a baby after an
IVF or ICSI treatment; the horizontal axis shows after how many
attempts.
Example: of the 100 women in the 20 to 29 age group who started
with IVF – ICSI, 37 may be expected to have given birth to a baby
after the first attempt, 60 after the second attempt and 73 after
the third attempt.
In terms of ‘average’ success – i.e. all ages and irrespective of the
number of attempts – the following figures are available. Of 3,600
pick-ups performed in the course of one year by the CRG at UZ
Brussel, nearly 90% produce eggs which are fertilized to become
viable embryos ready for transfer to the uterus. These embryo
transfers produce a pregnancy in 30 percent of cases on average.
So almost 25% of the original pick-ups result in the live birth of
a baby.
THEORY
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