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Reproduction
A training resource for Healthcare Professionals provided by Merck
©Merck Serono Limited 2015. All rights reserved.
Original version devised and written by Acteon Communication and Learning
Revised in house by Merck Medical Department
D.O.P. December 2015 RH14-0047b
Module 1: Reproduction
Contents
Introduction and learning objectives................................................................................................................................................................................ 05
Normal reproduction............................................................................................................................................................................................................................................... 06
Some basic definitions........................................................................................................................................................................................................................................ 06
Anatomy of the female reproductive system................................................................................................................................................... 06
The ovaries................................................................................................................................................................................................................................................................. 07
The fallopian tubes.................................................................................................................................................................................................................................. 08
The uterus................................................................................................................................................................................................................................................................... 09
Hormones of the female reproductive system.............................................................................................................................................. 10
Oestrogen.................................................................................................................................................................................................................................................................... 11
Progestogens........................................................................................................................................................................................................................................................ 12
Androgens................................................................................................................................................................................................................................................................... 12
Cyclical hormone secretion and the feedback mechanism.............................................................................. 13
Reproduction and the female menstrual cycle............................................................................................................................................ 14
The menstrual cycle................................................................................................................................................................................................................................................... 16
Follicular development................................................................................................................................................................................................................... 17
The follicular phase – hormonal influences....................................................................................................................................... 20
– Recruitment.................................................................................................................................................................................................................................................... 21
– Selection................................................................................................................................................................................................................................................................. 21
– Early dominance.................................................................................................................................................................................................................................... 21
– Dominance – final maturation............................................................................................................................................................................... 22
– Changes in the uterus during the follicular phase..................................................................................................... 24
Ovulation...................................................................................................................................................................................................................................................................... 24
– Changes in the uterus at ovulation............................................................................................................................................................. 24
The luteal phase............................................................................................................................................................................................................................................. 26
– Changes in the uterus during the luteal phase.................................................................................................................. 27
Summary............................................................................................................................................................................................................................................................................................. 28
Implantation and pregnancy........................................................................................................................................................................................................ 29
Fertilisation and implantation................................................................................................................................................................................................... 29
More on early development of the embryo....................................................................................................................................... 30
The male reproductive system............................................................................................................................................................................................................ 32
Anatomy of the male reproductive system......................................................................................................................................... 33
– The testes.............................................................................................................................................................................................................................................................. 33
– The epididymis........................................................................................................................................................................................................................................... 34
– The vas (ductus) deferens.................................................................................................................................................................................................. 34
– The prostate and seminal vesicle....................................................................................................................................................................... 35
– Penis................................................................................................................................................................................................................................................................................. 35
Production of sperm cells – spermatogenesis............................................................................................................................... 36
The structure of the sperm cell..................................................................................................................................................................................... 37
Hormonal control of male reproduction.................................................................................................................................................. 38
Glossary.................................................................................................................................................................................................................................................................................................. 39
References........................................................................................................................................................................................................................................................................................ 43
Module 1: Reproduction
Introduction and learning objectives
Infertility is a surprisingly common problem, whose causes can stem from a variety
of factors in either or both partner. Before looking at approaches to treating
infertility, it is important to understand how the reproductive system functions
normally, in both women and men. This is essential for an understanding of the
various treatments and hormonal protocols used today.
Module 1 describes reproductive physiology in both sexes, with an emphasis on
female reproductive mechanisms. Module 2 then goes on to look at how this can
go wrong, causing fertility problems for a couple.
After reading this first module, you should be able to:
name the structures that make up the female reproduction system, and
describe the role each plays in reproduction
explain the relationship between the gametes, ovary, oocyte, follicle and
follicular cells
name the pituitary and gonadal hormones that regulate the reproductive cycle,
and the hypothalamic hormone that influences the levels of these hormones
explain what is meant by positive and negative feedback (in terms of
hormone level regulation)
define the menstrual cycle and describe the key events occurring within it
name the main functional stages of development of the follicle
describe the changes in the ovary, uterus and in hormone levels throughout
the cycle
outline the events leading up to implantation of the embryo
describe the processes and hormones regulating male reproduction
state the key difference between the hormonal regulation of the male
and female reproductive process
understand the importance of the reproductive systems and hormones
to fertility treatment.
glossary
Infertility: Those couples who do
not achieve a pregnancy within
two years of regular sexual
activity. This group is made up
of those defined as sterile or
subfertile.
Fertility: Normal fertility is the
ability to achieve a pregnancy
within two years by regular
coital exposure.
Gamete: The mature
reproductive or germ cell – an
egg or ovum in the female, and
sperm in the male. Each gamete
contains half the total number
of chromosomes – i.e. only
23 chromosomes, instead of the
23 pairs of chromosomes (i.e. 46
in total) found in all the other
cells of the body.
Oocyte: The immature female
gamete, i.e. the cell that
develops to form the mature
ovum or egg.
Spermatozoon: A motile male
gamete usually with rounded
or elongated head and a
long posterior flagellum – it
joins with an ovum to form a
zygote.
Normal reproduction
In order to understand the causes of infertility, we need first to understand the
normal reproductive process. It will become clear that both the female and male
reproductive systems can go wrong at a number of sites, so reducing a woman’s
chance of pregnancy.
Some basic definitions
Reproduction in humans results in the creation of a new individual with half its
chromosomes from its mother, and half from its father. These parental chromosomes
are carried in the maternal and paternal sex cells, or gametes. In the female, the
gamete is called the oocyte; in the male, the gamete is the spermatozoon (plural:
spermatozoa, or sperm). As we shall see, the oocyte develops within the ovary into a
mature egg, known as the ovum; fertilisation of the ovum by a spermatozoon may
result in an embryo and a pregnancy.
Anatomy of the female reproductive system
The female reproductive system lies within the body cavity formed by the bones of
the pelvis. It consists of three main organs:
the ovaries – these produce the eggs, or ova
the fallopian tubes (or oviducts) – these lead from the ovaries and carry
the egg to the uterus
the uterus or womb – where the fertilised egg develops during pregnancy.
The cervix is the lower, narrower part of the uterus which opens into the vagina.
Ovum: A female gamete or egg.
Fertilisation: The penetration
of an egg by the sperm and
the resulting combining of
genetic material that develops
into an embryo.
Embryo: An egg that has been
fertilised by a sperm and has
undergone one or more cell
divisions.
Ovaries: Paired oval organs
in the female containing
thousands of immature
egg cells held within the
follicles; site of sex hormone
production (by follicles).
Module 1: Reproduction
The female reproductive organs
nice to know
Fallopian tubes
Fallopian tubes
More about oocytes1
Female infants are born with
about 1 to 2 million oocytes
(the precursors of the mature ova
that will develop in her lifetime).
Ovaries
Ovaries
Uterus
No new oocytes are formed after
birth and only a small percentage
mature into eggs (ova). The
oocytes that do not mature
degenerate. By puberty only
around 300,000 oocytes remain
within the ovaries.
Vagina
Uterus
Vagina
Rectum
Rectum
Bladder
Degeneration of the oocytes
progresses more rapidly as a
woman ages, and by menopause,
no oocytes remain.
Bladder
Myometrium
Fundus
Myometrium
Fundus
Fimbriae
Fimbriae
Ovary
Fallopian tube
Fallopian tube
Follicle
Ovary
Endometrium
Follicle
Body
Endometrium
Cervix
Body
Cervix
Vagina
Vagina
The ovaries
The ovaries are a pair of small, oval organs which lie just below the fallopian tubes
on each side of the uterus. Immature egg cells (oocytes) are held within fluid-filled
cavities called follicles in the wall of the ovaries. Each follicle is made up of a cluster
of cells around one oocyte; these follicular cells nourish and protect the egg. These
cells also secrete steroid sex hormones and are thus vital in the reproductive process,
as we shall see.
The follicle is much more than simply a sac holding the ‘egg-to-be’: its cells
produce essential reproductive hormones, and it is thus the functional unit of
the ovary.2
glossary
Fallopian tubes: A pair of slender
ducts through which eggs pass
from the ovaries to the uterus.
Uterus: Hollow, pear-shaped
reproductive organ found in
the low central region of the
woman’s pelvis; it is in the uterus
where the fetus develops during
gestation.
Cervix: Lower, narrow portion of
the uterus that opens into the
top end of the vagina.
Follicles: A fluid-filled sac located
just beneath the surface of the
ovary. It contains an oocyte and
cells that produce hormones. The
follicle increases greatly in size
and volume before ovulation,
at which time it matures and
ruptures to release the egg.
During a woman’s reproductive years, a single mature egg is normally released from
one of the ovaries every month (or around every 28 days, depending on the length
of the woman’s menstrual cycle); this is the critical event of ovulation. You will learn
more about this later. The ovum is then transported via the fallopian tube to the
uterus where it may or may not be fertilised.
The fallopian tubes
The fallopian tubes (or oviducts) are two J-shaped tubes that extend from the ovaries
to the uterus. The fallopian tubes play an active part in the reproductive process.
Each tube has a fan-like end made up of a fringe of finger-like projections called
fimbriae which catch the newly released egg.
The end of the tube near the ovary contracts to push the egg towards the uterus
(and incoming spermatozoa), whilst the end closest to the uterus contracts in the
opposite direction, to push sperm towards the egg. The two gametes normally meet
in the ampulla, the most common site of fertilisation. If fertilisation occurs, the
resulting embryo will travel down the fallopian tube (a journey taking a few days),
eventually reaching the uterus.
The fallopian tubes and their relation to the ovary
Fallopian tube
Ampulla
glossary
Ovary
Ovulation: The monthly release
of an egg from one of the ovaries.
Fimbriae
Fimbriae: Fringe of tissue at
the ovarian end of the fallopian
tube which catches the newly
released egg and sweeps it into
the fallopian tube.
The fallopian tubes are actively responsible for:
Ampulla: The middle portion of
the fallopian tube.
Uterus
•
•
•
•
•
Picking up a newly released egg
Providing nutrients and movement to the egg
Transporting sperm to the egg
Sustaining an environment for fertilisation
Moving a fertilised egg into the uterus.
Module 1: Reproduction
The uterus
The uterus, or womb, is the hollow, pear-shaped organ found in the low central
region of the woman’s pelvis. During the time the egg is developing within the
ovary each month, changes are also taking place within the uterus.
The uterus has a thick muscular wall, which can expand enormously during
pregnancy, and can contract very strongly during childbirth. Within this wall
is a lining of mucus-producing cells called the endometrium; this undergoes a
monthly cycle of changes in preparation for the embryo should the egg be
fertilised. If fertilisation does not occur, this lining is shed during the normal
menstrual cycle.
The lower end of the uterus connects to the vagina via a narrow passage called
the cervix. This passage is normally filled with cervical mucus, the consistency of
which varies throughout the woman’s monthly cycle:
around the time of ovulation, the mucus is thin and watery, to make it
easier for sperm to travel into the uterus and on to the fallopian tubes
after ovulation (or during pregnancy), the mucus becomes thick and
viscous through loss of water, and hostile to sperm – to protect the uterus
from foreign material.
glossary
Endometrium: The mucous
membrane lining the uterus that
plays a vital role in nourishing
and supporting the developing
embryo.
glossary
Hypothalamus: Part of the
brain above the pituitary that
regulates many bodily functions,
including hormone release by the
pituitary; integrates incoming
hormonal and nervous signals
and secretes releasing-hormones
in response.
Pituitary gland: Gland lying at
the base of the brain, beneath
the hypothalamus, that secretes
many hormones, including the
gonadotropins FSH and LH.
Gonadotropin-releasing
hormone (GnRH): Hormone
produced by the hypothalamus
that stimulates the pituitary
to release gonadotropins
(luteinising hormone and
follicle-stimulating hormone).
Follicle-stimulating hormone
(FSH): The pituitary hormone
responsible for stimulating
follicle growth and egg
development as well as
production of oestrogen in
women. In men, FSH helps
stimulate the testes to
manufacture sperm.
Luteinising hormone (LH):
The hormone that triggers
ovulation and stimulates
the corpus luteum to secrete
progesterone.
Gonads: The organs that
produce gametes – the testes
in males and the ovaries in
females.
Hypothalamic–pituitary–
gonadal axis: A term used
to describe the effects of
the hypothalamus, pituitary
gland, and gonads as if
acting as a single entity – it is
important in the development
and regulation of a number
of vital body systems,
including development and
reproduction.
Hormones of the female
reproductive system
All the events of the reproductive process are intricately regulated by the action
of hormones, ‘chemical messengers’ secreted by specialised glandular tissue in one
part of the body that act on tissues or organs at another site within the body.
The hormones controlling reproduction are ultimately regulated by a structure at
the base of the brain, the hypothalamus. The cells of the hypothalamus secrete
substances that control the release of other hormones, called hormone-releasing
factors. These factors (also hormones) are carried in local blood vessels down to the
‘master gland’, the pituitary, lying, attached by a stalk, just below the hypothalamus.
The hypothalamic releasing factor of interest to us is gonadotropin-releasing
hormone, or GnRH.
GnRH binds to receptors on anterior pituitary gland cells, stimulating the cells
to synthesise and secrete two hormones: follicle-stimulating hormone (FSH)
and luteinising hormone (LH). Both FSH and LH stimulate the gonads (the
reproductive organs – the ovary and testis) and so are called gonadotropic
hormones. The whole hormonal system controlling reproduction is thus termed
the hypothalamic–pituitary–gonadal axis, in both males and females.
FSH and LH stimulate cells in the ovaries to produce steroid hormones:
oestrogens
progestogens
androgens, all described in the following pages.
context
It is important that you become familiar with these key reproductive hormones, and
how they interact, as understanding their roles will help you explain the modes of
action of different fertility treatments.
Another hormone involved in reproduction is the protein hormone prolactin. It is
also made in the pituitary, though unlike other pituitary hormones it is secreted
in large amounts when the links between the pituitary and hypothalamus are
disconnected. Regulation of secretion is therefore maintained by inhibition.2 High
levels of prolactin (hyperprolactinaemia) in men and women has profound effects
on reproductive function.2 You will learn more about this condition and how it is
treated in Module 2.
Module 1: Reproduction
The relationship between the hypothalamus and the pituitary gland
Hypothalamus
Pituitary gland
Hormone-releasing
factors secreted here
Pituitary hormones
released into bloodstream
Oestrogen
Oestrogen is the generic name for a family of female sex steroid hormones.
It occurs in several forms but in general oestrogen is responsible for female
sexual development and proliferation or renewal of the uterine endometrium
after this layer has been shed in days 1 to 5 of the monthly menstrual cycle.
The three major naturally occurring oestrogens in women are:
oestradiol 17β (E2) – the predominant form in non-pregnant women
oestriol (E3) – the primary oestrogen of pregnancy
oestrone (E1) – produced during menopause.
Like the other steroid hormones here, oestrogens are produced by the ovarian
follicles.
glossary
Oestrogen: The naturally
occurring female sex steroid
hormone produced by the ovaries
and responsible for development
of the reproductive organs and
secondary sexual characteristics,
as well as for the proliferation of
the endometrium.
Progestogen: Synthetic steroid
hormone similar in structure to
the naturally occurring female
sex hormone progesterone.
Androgens: Generic term
for male hormones (e.g.,
androsterone, testosterone).
Prolactin: A protein hormone
made in the pituitary, it is
secreted in large amounts
when the links between the
pituitary and hypothalamus
are disconnected, therefore
regulation of secretion is
maintained by inhibition.
Hyperprolactinaemia:
Abnormally high levels of
prolactin in the blood.
Oestradiol 17β (E2): One of the
three major oestrogens naturally
occurring in women – it has
a key role in reproduction and
development.
Progestogens
key point
Oestrogens, androgens and
progestogens are all produced
by different cells of the
ovarian follicles, described in
Figure 7 on page 18.
Progestogens are another family of female steroid sex hormones. They are secreted
in the second half of the cycle, produced by the follicle after it has released its ovum
and has transformed into the corpus luteum. The main progestogen is progesterone
which is primarily responsible for changing the endometrium to the secretory
stage when it is ready for implantation of a fertilised ovum and ongoing pregnancy
(gestation). Progesterone also stimulates development of the milk-producing lobules
in the breasts.
Androgens
Androgens are so-called ‘male’ sex steroids that are secreted by the adrenal gland in
both males and females. (In mature males however, most androgen (testosterone)
is produced in the testes, so that only 5% of the male’s total androgen production
comes from the adrenal gland.)
In females, adrenal androgens account for around half of the total androgen activity;
the rest is from androgens formed in the developing ovarian follicles. As we shall see,
these so-called male hormones become the precursor of all the oestrogens in the
woman’s body. Androgens are released by the ovaries into the bloodstream, and with
adrenal androgens, they promote growth of body hair at puberty.
In the next section we’ll look at the interactions between the two most important
steroid hormones (oestrogen and progesterone), the gonadotropins FSH and LH, and
the hypothalamic releasing factors, and how these regulate the woman’s monthly
menstrual cycle and potential fertility.
nice to know
Increased androgen in women
can give rise to conditions
such as acne, hirsutism and
menstrual irregularities.
Polycystic ovaries
(i.e. polycystic ovarian
syndrome, see Module 2) are
a common cause of increased
androgen in women.
Module 1: Reproduction
Cyclical hormone secretion and the
feedback mechanism
The hypothalamic–pituitary–gonadal axis and sites of hormonal feedback
Hypothalamus
GnRH
key point
Hormonal levels are regulated
by feedback mechanisms,
which turn up or turn down
their production.
FSH + LH
Anterior
pituitary
gland
Developing follicle
and corpus luteum
Ovary
Oestrogen
Progesterone
Growth of
reproductive organs
and endometrium
Maintenance
and secretion
of endometrium
Uterus
Secretion of gonadotropin-releasing hormone, GnRH, by the hypothalamus
is altered under the influence of feedback from the circulating steroid hormones, oestrogen and progesterone.
Normally the feedback to the hypothalamus is negative: presence of the
steroid hormones reduces GnRH release.
But at one key point in the cycle it switches briefly to positive feedback,
so that the steroid stimulates GnRH release. This is the key to the release
of the mature ovum from the ovarian follicle during ovulation, described
on page 24.
glossary
Corpus luteum: The ‘yellow body’
formed from the ruptured follicle
after ovulation; composed of
remaining granulosa cells that
are transformed into luteal cells
by the action of LH.
Progesterone: Naturally
occurring female sex
steroid hormone primarily
responsible for the transition
of the endometrium from its
proliferative to its secretory
stage, regulating fertility.
Testosterone: Male hormone
produced primarily by the
testes that is the main androgen
responsible for inducing and
maintaining male secondary
sex characteristics.
Reproduction and the female menstrual cycle
Each month the reproductive system of a normal woman of reproductive age
undergoes a series of changes known as the menstrual cycle. These changes allow
the release of a mature egg from the ovary, and prepare the body for a possible
pregnancy. In outline:
An egg develops inside a follicle within the ovary
As the follicle matures, it forms a reddish bulge visible on the surface of the
ovary. A hole forms for expulsion of the mature egg, which is released during
ovulation at mid-cycle
When released into the abdominal cavity, the egg is drawn into the fallopian tube
by the tentacle-like fimbriae; cells lining the inner surface of the fallopian tubes
waft the egg towards the uterus with their microscopic hairs (cilia)
At the same time as the ovum is developing in the ovary, the lining of the uterus
develops in readiness to receive and nurture the fertilised egg
If active sperm are present fertilisation usually takes place within the
fallopian tube
Contractions of the wall of the fallopian tube move the fertilised egg (blastocyst)
towards the uterus where it will become implanted in the endometrium, and a
pregnancy will have begun
If fertilisation has not occurred, the endometrium breaks down and is shed; this
is the process of menstruation – the discharge of blood, endometrial cells and
mucus from the vagina – during the menstrual period.
The length of the menstrual cycle is calculated from the first day of menstrual
bleeding to the day the next month’s bleed begins. This cycle typically lasts 28 days,
including 4–5 days of bleeding; however it can vary greatly between individuals
(cycles of 23 days or 35 days are ‘normal’). The variability occurs in the first half of
the cycle; the second half of the cycle is usually a fixed 14 days after ovulation.
We will now look at these events in more detail.
Module 1: Reproduction
A summary of events in the average menstrual cycle
9
10
5
4
3
Development of
egg and preparation
of uterus
8
7
6
Shedding of endometrium
(Menstruation)
11
12
2
1
13
Days
28
14
15
27
21
23
22
Fertilisation
Pregnancy
18
19
20
No fertilisation
17
25
24
26
16
Ovulation
The menstrual cycle
During the menstrual cycle changes are taking place both in the ovary and
the uterus.
The phases of the menstrual cycle
Ovarian phases
Follicular phase
Luteal phase
Follicle
develops
Events at the ovary
Corpus luteum
develops
Ovulation
Menstruation
Uterine phases
Menstrual
0
Corpus luteum
degenerates
Proliferative
5
Secretory
14
21
28
The ovarian cycle of changes is divided into:
the follicular phase – maturation of (normally one) follicle containing an egg
ovulation – release of the mature egg, leaving a ruptured empty follicle
the luteal phase – development of the corpus luteum from the follicular remains.
The uterine cycle of changes is divided into:
the menstrual phase – vaginal discharge of blood, endometrial cells and mucus
the proliferative phase – endometrial cells proliferate and form a new functional
layer, and the consistency of cervical mucus changes to encourage the passage
of sperm into the uterus
the secretory phase – the endometrial glands secrete a glycogen-rich ‘milk’ in
preparation for the embryo.
The following pages explore these changes in more detail, looking at hormonal as
well as physiological changes. First we need to look at the follicle more closely and
define a few key terms relating to its development.
Module 1: Reproduction
Follicular development
You will need to know the stages that the developing follicle goes through when
considering how LH and FSH act on the maturing follicle to stimulate ovulation.
These pages summarise these developmental stages.
The primordial follicles containing the primary oocytes remain dormant and
unchanged until puberty. Then at the start of the menstrual cycle (once these have
become established), a group of primordial follicles in the ovary start to develop.
Follicular development 2 (note that days are approximate as the first half of the cycle can vary)
1: Primordial follicle
2: Pre-antral follicle
Membrana propria
Zona pellucida
Germinal vesicle
Granulosa cells
Oocyte
Theca cells
Diameter: <500 µm (< 0.5 mm)
Diameter: 20 µm
Oocyte itself increases to its final size of 60–120 µm at this stage
The ‘eggs-to-be’ present at birth and throughout the cycle;
some will be recruited each month into primary follicles, which
start development towards maturity.
Tiny follicles (also called secondary follicles); continue to
develop from the primordial follicle, with potential of becoming
mature follicles.3
Granulosa cells surround the oocyte; these will develop to become
a source of oestrogen when stimulated by FSH; no steroid receptors
present yet.
The granulosa cells divide into several layers, and a protective shell
forms around the primary oocyte – important for controlling entry of
the sperm into the oocyte during fertilisation.
Granulosa cells produce anti-Müllerian hormone (AMH), which
depresses recruitment of primordial and pre-antral follicles.
When 3-6 layers of granulosa cells have formed around the oocyte,
cells from the surrounding ovarian tissue cluster around the follicle
to form a secretory layer of cells called the theca.
Theca cells develop to become source of androgen when stimulated
by LH; no steroid receptors present yet.
glossary
Granulosa cells: FSH-sensitive
cells surrounding the oocyte;
those of the dominant follicle
convert androgens to estrogens
under the influence of FSH.
Anti-Müllerian hormone
(AMH): A member of the
transforming growth factor
β family of growth and
differentiation factors. In the
ovary, AMH has an inhibitory
effect on primordial follicle
recruitment as well as on the
responsiveness of growing
follicles to follicle-stimulating
hormone (FSH).
Theca cells: LH-sensitive cells
surrounding the outside of
the follicle; those of the
dominant follicle convert
cholesterol to androgens
under the influence of LH.
Inhibin B: A glycoprotein
hormone that is secreted by
the pituitary gland and
inhibits the secretion of
follicle-stimulating hormone
– in the male it is secreted
by the Sertoli cells and in the
female by the granulosa cells.
Module 1: Reproduction
Recruited follicles continue their growth (now also called
tertiary follicles), developing fluid-filled space between follicular
cells – the antral space; visible around day 1–6 of menstrual cycle.
Granulosa and theca cells have proliferated; thecal cells now
comprise two layers – outer theca externa and inner theca interna
(latter contains blood vessels, not shown). There are no vessels inside
the granulosa layer. FSH and LH receptors have developed on
granulosa cells and theca interna cells respectively.
The theca interna cells respond to LH by secreting androgens, the
basis for oestradiol production.
Under the influence of FSH, granulosa cells produce inhibin B, which
enhances FSH stimulation of the granulosa cells; inhibin B secretion
declines after the mid-antral follicular stage.
3: Early antral follicle
4: Late (expanded) antral follicle
Theca interna
Theca externa
Antrum
Cumulus
Diameter: 2–7 mm
context
Levels of both anti-Müllerian hormone (AMH) and inhibin B
may be used as an indication of the number of follicles in
the ovary (i.e. as a test of ovarian reserve, and a predictor of
a woman’s response to ovarian stimulation). You will learn
more about this in Module 2.
Recruited follicles continue to grow (may now be known as
‘expanding’ follicle); visible day 6–10 (size 7–10 mm). In a
natural cycle only one follicle (occasionally two) now emerges
as the dominant follicle (see below).
FSH and LH receptors are still present; plasma oestrogen levels
are 100–200 pmol/L.
By day 10–12 it has grown to around 10–20 mm diameter
(the ‘expanded’ follicle).
The antrum is now fully developed, leaving oocyte surrounded
by distinct and denser layer of granulosa cells, the cumulus. The
cumulus will provide the matrix that carries the egg out of the
follicle at ovulation.
FSH and LH receptors are still present; plasma oestrogen levels
are high – 200-400 pmol/L.
Diameter: 7–10 mm (expanding); 10–20 mm (expanded)
Large antral and pre-ovulatory follicles secrete inhibin A, which
enhances LH-induced androgen production in thecal cells.
The selected follicle from the recruited cohort is usually the one
that is most sensitive to FSH – i.e. has the most FSH receptors. The
other follicles that have developed now regress and degenerate.
At day 13–15 the dominant follicle is fully mature; it is
now known as the pre-ovulatory or Graafian follicle). Its diameter
is now 20–25 mm.
FSH and LH receptors are still present; plasma oestrogen levels
are maximal, at ≥800 pmol/L.
The LH surge causes the oocyte to undergo cell division known as
meiosis, in which the total number of chromosomes in the nucleus
is halved (from 46 – 23 pairs) in readiness for fertilisation.
context
The raised E2 levels at the late antral stage are used as a
measure of follicle numbers and size during IVF cycles.
In summary:
primordial (immature) follicles are present at birth in the baby’s ovaries; each
month, several hundred are recruited to give rise to …
primary follicles, which develop into…
pre-antral (secondary) follicles, which grow into…
antral (tertiary) follicles, one (or occasionally two) of which is selected to
become dominant and to continue development to become the…
fully mature, pre-ovulatory follicle (sometimes called the Graafian follicle).
We shall now return to the changes taking place in the hypothalamic–pituitary–
gonadal axis during the menstrual cycle – i.e. hormonal and uterine changes.
The follicular phase – hormonal influences
The dominant hormones in the follicular phase are follicle-stimulating
hormone, FSH, and oestrogen.
ypothalamus: Secretes small pulses of GnRH, approximately one
H
pulse per hour2
Pituitary: Responds by producing small amounts of FSH and LH,
again in pulses
Ovary: Developing follicles secrete small amounts of oestrogen in
response to FSH and LH
The period before ovulation is characterised by oestrogen dominance2 – it is
the time of follicular recruitment and development of a single (or sometimes
two) dominant follicle(s).
During the follicular phase the follicular cells surrounding the oocyte change as the
stages of development described previously take place. These changes are influenced
by fluctuations in the levels of steroid hormones and gonadotropins.
During the days just before menstruation, all hormone levels are relatively low. FSH
and LH levels start to rise during menstruation – at the start of the follicular phase
– and they act together to stimulate the development of a group of primordial
(immature) follicles in the ovary. Each month a few hundred primordial follicles will
start to grow, though only a few will be sufficiently developed at the appropriate
time – 1-2 days prior to menstruation – to respond to gonadotropins and progress to
the next phase.
Module 1: Reproduction
Recruitment
Normally throughout the cycle, oestrogen signals the hypothalamus to turn
down GnRH production (negative feedback, designed to prevent excess hormone
secretion).
Since oestradiol is relatively low at the start of the cycle, FSH and LH levels are
able to increase. LH stimulates the theca cells to produce androgen (testosterone,
the male sex hormone), the basis for oestrogen production; oestradiol levels thus
start to rise. This increases negative feedback and FSH levels start to fall at around
day 5 or 6.
The FSH that is present continues to stimulate the follicles, which continue to grow;
developing FSH receptors in the granulosa cell layer.
Selection
glossary
2-cell, two-gonadotropin
model: Theory that both thecal
and granulosa cells (2 follicular
cell types) and LH and FSH
(2 gonadotropins) are needed
for full ovarian stimulation.
Around day 6-7 of the cycle, the follicle with the highest number of FSH receptors
becomes the dominant follicle. As FSH levels fall, only the dominant follicle can
maintain growth; the others die.
Early dominance
Under the influence of FSH, the granulosa cells of the dominant follicle convert
androgen to oestrogen, via the aromatase enzyme (in a process known as the
2-cell, two-gonadotropin model, illustrated on the next page). The follicle thus
secretes increasing amounts of oestrogen (and small amounts of progesterone).
Plasma oestrogen levels continue to rise sharply over the next 7 days or so. At
days 10–13, plasma oestrogen is around 200–400 pmol/L.2
The 2-cell, two-gonadotropin model states that both thecal and granulosa cells
(2 follicular cell types) and LH and FSH (2 gonadotropins) are needed for full
ovarian stimulation.4
key point
Recruitment is the term for the
selection of the primordial and
primary follicles at the end of
the previous luteal phase of a
cycle; these follicles are ‘rescued’
from atresia (degeneration) by
the action of FSH (although LH is
needed for them to become fully
functional follicles; see later).
Primordial follicles mature into
pre-antral follicles in a constant
trickle throughout the woman’s
adult reproductive life.2
The hormonal changes and follicular development during the
follicular phase
Follicular phase
LH
Theca cell
FSH
cholesterol
+
pregnenolone
Nucleus
androgens
diffusion through the
basement membrane
Granulosa cell
androgens
(aromatase)
Nucleus
+
estrogens
circulation
Estradiol
Steroid hormone
levels
Progesterone
FSH
Gonadotropin
levels
nice to know
Meiosis (cell division by
reduction) involves many
different stages, too
complex to go into in this
module. However, you will
need to recognise the term
metaphase 2 (M2 or MII),
when you read clinical
studies. This refers to a
late stage in the process
of meiosis, when the
oocyte’s division in
preparation for fertilisation
is quite advanced.
LH
Primordal
Preantral
Early antral
Late antral
(dominant)
Mature antral
(preovulatory)
Recruitment
Selection
Early
dominance
Dominance –
final maturation
Menstrual
0
Proliferative
5
14
Dominance – final maturation
Around day 13 oestradiol levels peak towards the end of the follicular phase, when
levels reach 800 pmol/L or more4 (i.e. they have more than doubled). At this critical
moment, oestradiol feedback switches very briefly from negative to positive. The
hypothalamus responds by secreting much more GnRH, resulting in a surge of LH
(and to a lesser extent FSH) from the pituitary.
It is this LH surge (at around day 13) that causes rupture of the mature follicle and
release of the egg into the peritoneal cavity from where it is drawn into the fallopian
tube. This is the process of ovulation: it occurs around a day after the LH surge.
Module 1: Reproduction
nice to know
The 2-cell, two-gonadotropin model of oestrogen synthesis by
the developing dominant ovarian follicle 2
pregnenolone
The 2-cell, two-gonadotropin
model theorises that each
gonadotropin acts solely on a
separate set of ovarian follicle
cells:5
androgens
• FSH on granulosa cells and
• LH on theca cells.
LH
Theca cell
FSH
cholesterol
+
Nucleus
diffusion through the
basement membrane
Granulosa cell
androgens
(aromatase)
Nucleus
+
estrogens
circulation
Step 1: LH binds to its receptor in the follicle’s theca interna cell
Step 2: Inside theca cell, LH activates the enzyme that converts cholesterol
to pregnenolone, which is then converted to androgens (androstenedione
and testosterone)
However, in the late stages of
follicle development, facilitated
by oestrogens, LH receptors
are expressed by granulosa
cells making them receptive to
LH stimulation.5
LH is then capable of exerting
its actions on both theca and
granulosa cells. At this stage
LH can exert virtually all of
the FSH physiological actions
on granulosa cells, including
stimulation of the aromatase
system.5
This stresses the importance
of LH for follicle maturation
and development which is
particularly relevant during
ovulation induction treatment.4
ANDROGEN PRODUCTION IS STIMULATED BY LH
Step 3: Theca androgens then diffuse through the basement membrane into
the follicle’s granulosa cell
Step 4: FSH binds to its receptor on the granulosa cell
Step 5: Inside the granulosa cell, FSH activates the aromatase enzyme,
which converts androgens to oestrogens (androstenedione is converted to
oestrone and testosterone is converted to estradiol-17β)
key point
Follicular growth and maturation
is dependent upon the dynamic
interplay between both
gonadotropins, FSH and LH.
Key events such as follicular
recruitment and dominant
follicle selection rely upon both
either FSH or LH activity and
on granulosa cell LH receptor
status at different stages of the
follicular phase.5
Changes in the uterus during the follicular phase
In the follicular phase of the cycle, the uterus undergoes the menstrual phase
and the proliferative phase. In the menstrual phase, days 1–4, the dead lining is
shed during menstruation. In the proliferative phase, days 5–13, increasing levels
of oestradiol produced by the maturing follicle induce proliferation of
the endometrium, forming a new functional layer containing (as yet inactive)
glands. Thin, watery cervical mucus is secreted to encourage the passage of sperm
into the uterus.
Ovulation
As the dominant follicle grows, it moves towards the surface of the ovary. Its wall
becomes thinner as it swells with antral fluid, until towards the end of the follicular
phase it has reached a size big enough for it to be ovulated (released from the
ovary). This critical size is around 20–25 mm across;2 it usually occurs around
day 12 of the cycle, 1–2 days before the actual event of ovulation.
Ovulation then occurs on around day 14, when the mature Graafian follicle bursts,
breaking through the surface layer of the ovarian wall (the germinal epithelium).
The ovum is released into the peritoneal cavity, within range of the sweeping
fimbriae of the fallopian tubes.
As you have seen, the LH surge is essential for ovulation, the onset of LH surge
usually precedes ovulation by 36 hours. The peak, on the other hand preceded
ovulation by 10-12 hours.6 Some clinical signs can be used to detect the onset
of ovulation. These can include:
ain felt in the region of the ovary as it is stretched by the growing follicle –
p
about 24-48 hours before ovulation
a rise in basal body temperature
alteration in the cervix and its secretions.
Changes in the uterus at ovulation
At ovulation the secretions of the cervix change. The mucus which has been sticky
and viscous, in effect forming a plug, becomes more fluid and runny to allow an easy
pathway for sperm to pass into the uterus.
Module 1: Reproduction
Follicular, hormonal and uterine events during the menstrual cycle
Ovarian phases
Follicular phase
Luteal phase
Corpus luteum
develops
Follicle
develops
Events at the ovary
Corpus luteum
degenerates
Ovulation
Menstruation
Estradiol
Steroid hormone
levels
Progesterone
FSH
Gonadotropin
levels
LH
Endometrial
changes
Uterine phases
Menstrual
0
Proliferative
5
Secretory
14
21
28
The luteal phase
The dominant hormones in the luteal phase are luteinising hormone (LH)
and progesterone.
ypothalamus: Now again receives negative feedback from oestrogen;
H
GnRH release falls
Pituitary: Levels of LH and FSH secretion fall
Ovary: Remaining LH acts on granulosa and theca cells, transforming
remains of follicle into corpus luteum, which secretes high levels of
progesterone until it withers
The period after ovulation is characterised by progesterone dominance.2
glossary
Corpus luteum: The ‘yellow body’
formed from the ruptured follicle
after ovulation; composed of
remaining granulosa cells that
are transformed into luteal
cells by the action of LH.
The second half of the cycle is the time between ovulation and the next
menstruation; it usually lasts 14 days, irrespective of the woman’s cycle length.
This is determined by the lifespan of the corpus luteum (‘yellow body’) – a body
formed when the remaining granulosa cells of the collapsed follicle are transformed
into luteal cells by the action of LH. These cells secrete the hormones characteristic
of this second phase of the menstrual cycle.
The remains of the ruptured follicle collapse after ovulation, and LH stimulates
the granulosa cells to divide and become yellow, or to luteinise (hence ‘luteinising
hormone’), i.e. to change into luteal cells. These cells form the corpus luteum, which
over the next 10 days secretes high levels of progestogens (mainly progesterone)
and estrogens (mainly oestradiol) in response to LH. These sex hormones:
(both) inhibit pituitary LH and FSH release by negative feedback
(both) maintain endometrial lining
(progesterone) stimulates mucus secretion from the endometrium, and thickens
cervical mucus
fall rapidly after the corpus luteum degenerates around day 25, if fertilisation
does not occur and implantation (the attachment of the embryo to the
endometrium) has not begun.
The fall in progesterone and oestradiol levels relaxes negative feedback at the
hypothalamus, allowing FSH and LH secretion to rise again; falling progesterone also
causes shedding of the endometrium (menstruation), and the start of next cycle.
Module 1: Reproduction
Changes in the uterus during the luteal phase
In the luteal or secretory phase the progesterone secreted by the corpus luteum
stabilises the endometrium, preventing further growth, and matures it ready
for implantation of an embryo; the glands of the endometrium grow and coil.
A few days into the luteal phase, the glands now secrete a glycogen-rich ‘milk’
in preparation for the embryo.
Progesterone also causes the cervical mucus to become glutinous and thick once
again, reducing sperm motility and inhibiting passage of sperm up the cervix to
the uterus.
If no embryo has been formed, the late luteal fall in steroid hormone levels causes
the collapse of the blood vessels supplying the endometrium. The functional
endometrium dies as its arteries constrict, blood leaks from the damaged vessels,
and the lining is shed. Menstruation occurs, marking the first day of the next
menstrual cycle.
Summary
The hormonal changes and feedback mechanisms controlling the ovarian cycle can
be summarised as follows:
1. At the end of the preceding menstrual cycle, regular GnRH pulses are produced
by the hypothalamus because FSH, LH, progesterone and oestradiol levels are low,
so no feedback inhibition exists. The GnRH pulses stimulate pulsatile release of
FSH and LH.
2. The relatively low FSH and estradiol levels during the first days of the follicular
phase work synergistically to stimulate the growth of a cohort of FSH-sensitive
pre-antral follicles. In this relatively low oestrogen environment, rising FSH levels
further stimulate follicular growth.
3. Around the time the dominant follicle is selected (around day 7 or 8),
oestradiol levels are still exerting a negative feedback effect on pituitary FSH
and LH secretion.
4. The dominant follicle continues to grow and produces increasing amounts of
oestradiol, which reaches a critically high level at mid-cycle. This high oestrogen
reverses the steroid’s feedback function: it now has a positive feedback effect at
the hypothalamus, which triggers a surge in FSH/LH release from the pituitary.
The LH surge causes final maturation of the oocyte and ovulation.
5. Oestrogens continue to be produced, and progesterone is produced by the corpus
luteum – a body formed when the remaining granulosa cells of the collapsed
follicle are transformed into luteal cells – during the luteal phase. Blood levels
of these sex steroids:
initially rise to high levels, inhibiting gonadotropin secretion
fall rapidly after degeneration of the corpus luteum, if pregnancy
has not occurred.
6. T he drop in the progesterone level causes the breakdown of the thickened
endometrial layer, leading to menstrual bleeding.
7. L ow blood levels of gonadotropins, oestrogen and progesterone lead to renewed
GnRH secretion from the hypothalamus, and the ovarian cycle begins once again.
Module 1: Reproduction
Implantation and pregnancy
After sexual intercourse, spermatozoa enter the uterus from the vaginal canal and
move towards the fallopian tubes – along which the egg is moving towards the
uterus. Only a few hundred of the 300 million or so spermatozoa ejaculated may
reach the egg.2 A single spermatozoon may penetrate the egg to fertilise it; this is
the fusing of the nuclear material of the egg and sperm. If fertilisation occurs, an
embryo is formed and cell division begins within it.
Note: the ovum is only capable of being fertilised within 24 hours after release into
the fallopian tube following ovulation.
Fertilisation and implantation
If implantation occurs (see below), the developing embryo prevents the
disintegration of the corpus luteum by producing the hormone human
chorionic gonadotropin (hCG). The corpus luteum can then continue to produce
the oestrogen and progesterone essential to maintain the endometrium and prevent
further ovulations or conception. This endocrine function is taken over by the
placenta at around 7-9 weeks of gestation.
The embryo continues its journey down the fallopian tube and, about 3 days after
fertilisation, emerges into the uterus. Cell division continues within the embryo,
while a supporting layer of cells called the trophoblast grows around it.
About 7 days after fertilisation the trophoblast attaches itself to the endometrium
and sinks into it. This is the process of implantation: it occurs when the endometrium
is well into its secretory phase. The endometrial secretions provide a source of
nutrients for the embryo until it can form links with the mother’s blood supply.
The trophoblast and its surrounding tissue containing the embryo are called the
chorion. Later this develops into the placenta which links the growing foetus to its
mother’s circulatory system.
The early stages of pregnancy
Development of embryo as it
passes along fallopian tube
Trophoblast
Fertilisation
Ovulation
Chorion
glossary
Human chorionic gonadotropin
(hCG): Hormone made by the
developing embryo soon after
conception and later by the
placenta. Its role is to prevent
the disintegration of the
corpus luteum of the ovary
and thereby maintain
progesterone production, critical
for pregnancy.
Trophoblast: The outer layer
of the blastocyst that supplies
nutrition to the embryo,
facilitates implantation by
eroding away the tissues of the
uterus with which it comes in
contact allowing the blastocyst
to sink into the cavity formed
in the uterine wall.
Chorion: Highly vascular outer
membrane that surrounds the
embryo.
nice to know
Human chorionic gonadotropin
gets its name from the word
chorion, the membrane
surrounding the embryo, which
secretes this hormone (and is
the precursor of the placenta).
More on early development of the embryo
Fertilisation normally occurs in the ampulla of the fallopian tube. This process has
many steps, but ultimately it depends on a healthy spermatozoon penetrating the
zona pellucida of the ovum. This results in mixing of the 23 chromosomes of each
of the two gametes, bringing the number to the full diploid complement of 46
chromosomes (23 pairs). The fertilised egg is now called a zygote. This immediately
begins to divide by mitosis (normal cell division, as opposed to meiosis, reduction
division when the chromosome set is halved to form the gamete).
The zygote divides into two cells called blastomeres (the two-cell stage) as the
embryo continues its journey down the fallopian tube. The blastomeres continue
their mitotic division, increasing the number of embryonic cells from 4 to 8 and
then 16. At the 16-cell stage the embryo is known as a morula; this enters the
uterus around 3 days after fertilisation.
The stages of embryo development
Morula
Zygote
Implantation
glossary
Diploid: Cells with two copies of
each chromosome, usually one
from the mother and one from
the father; human diploid cells
have 46 chromosomes.
Blastocyst
Uterine cavity
Fertilisation
Ovulation
Zygote: a cell formed by the
union of two gametes.
Mitosis: Process of cell division
by which a cell separates the
chromosomes in its cell nucleus
into two identical sets in
two nuclei.
Blastomeres: type of cell
produced by division of the
egg after fertilisation.
Morula: An embryo at an
early stage of embryonic
development.
Module 1: Reproduction
Endometrium
Soon after entering the uterus, it develops a cavity, forming an inner and outer layer
of cells. The outer layer is the trophoblast: this will form the placenta. The inner layer
is the embryoblast: this cell mass will form the embryo itself. Now the morula is
called a blastocyst.
The blastocyst implants itself within the body of the uterus by binding to the
endometrium. The embryoblast usually lies nearer the endometrial wall and the
blastocyst cavity closer to the lumen of the uterus (see diagram). The trophoblast
now grows rapidly, gaining its nutrition from the glycogen-rich fluid secreted by the
endometrial glands that were formed under the influence of progesterone from the
corpus luteum. It divides into two layers, one of which (the syncytiotrophoblast,
the layer nearest the endometrium) forms finger-like projections that invade the
endometrium to secure the blastocyst firmly in place within the uterus.
The pregnancy has now begun.
context
One form of assisted reproductive technology involves embryo transfer after in vitro
fertilisation (see Module 3). The transferred embryo is usually at morula stage, and
is replaced into the uterus at day 3 after fertilisation. However, some clinics may also
offer blastocyst transfer, where the fertilised eggs are left to mature for five to six
days and then transferred.
The next section turns to the male reproductive system, but in less detail.
glossary
Embryoblast: The mass of cells
inside the primordial embryo
that will eventually give rise
to the definitive structures of
the fetus.
Blastocyst: An early stage of
development of the embryo
shortly after fertilisation; the
stage when it moves into the
uterus for implantation.
Syncytiotrophoblast: Outer
layer of trophoblasts that forms
finger-like projections that
invade the endometrium to
secure the blastocyst firmly in
place within the uterus.
The male reproductive system
Male reproductive physiology is simpler than that of the female: there is no monthly
cycle of hormonal or structural changes, and no ‘window’ of fertility comparable to
ovulation. Thus a normal man can be fertile at any time. Interestingly, the pituitary
hormones involved in male puberty and reproduction are exactly the same as those
in the female – namely FSH and LH.
The male reproductive system has two important functions to perform:
1. production of sperm (the male gametes) – spermatogenesis
2. expulsion of sperm into the female’s vagina – ejaculation.
After puberty, the testes begin to produce sperm – and continue to do so throughout
the man’s lifetime. Sperm production is regulated by both the pituitary hormones
FSH and LH, and the gonadal hormone, testosterone.
The reproductive hormones and their function in males and females
Hypothalamus
Pituitary gland
GnRH
LH + FSH
‘Feedback’
hormones
‘Feedback’
hormones
or
Testes
Ovaries
Sperm cells
Egg cell
Testosterone
Voice ‘breaks’
growth of muscle tissue
enlargement of genitalia
facial, pubic & axillary hair
Module 1: Reproduction
Oestrogen
Broadening of hips
menstruation begins
development of breasts
pubic and axillary hair
Anatomy of the male reproductive system
The male reproductive system consists of the following parts:
The testis (plural: testes) – produces spermatozoa (sperm)
The epididymis at the top of each testis – stores and matures the sperm
The ejaculatory duct – ductus deferens or vas deferens – transmits sperm from
the epididymis to the penis
The prostate and seminal vesicles – secrete seminal fluid to support and protect
ejaculated sperm
The penis – following erection can penetrate the vagina and deposit sperm in
the vagina, to reach the cervix.
Relationship of the male reproductive organs
Bladder
Seminal vesicle
Prostate
Ampulla
Prostatic urethra
Ejaculatory duct
Bulbo-urethral
gland
Corpora cavernosa
Penile urethra
Vas deferens
Efferent ductules
in head of
epididymis
Glans
penis
Epididymis
Epididymal duct
Corpus
spongiosum
Seminiferous tubules
Testis
Vas deferens
emerging from
tail of epididymis
Terminal sections of
seminiferous tubules
The testes
The testes are the primary sex organs in the male. Each testis is an oval-shaped
organ, situated outside the body cavity in a sac called the scrotum. This location
keeps their temperature 2–3°C lower than body temperature, an essential
requirement for sperm production.7 The production of sperm is the major function
of the testes and if the temperature is too high, this function ceases.
Sperm are produced in response to gonadotropins from the pituitary gland and
testosterone from the testes’ own Leydig cells. Each testis consists of hundreds of
tightly coiled seminiferous tubules that produce the sperm.
glossary
Scrotum: The external sac that
contains the testes.
Leydig cell: A cell of interstitial
tissue of the testis that is usually
considered the chief source
of testicular androgens and
especially testosterone.
Seminiferous tubules: Coiled
threadlike tubules that make
up the bulk of the testis
and are lined with a layer of
epithelial cells from which the
spermatozoa are produced.
Each tubule is lined with epithelium containing two types of cells:
nice to know
During development, the
foetal Sertoli cells secrete
anti-Müllerian hormone.
This hormone suppresses the
development of the female
reproductive ducts (the
Müllerian ducts that form
the fallopian tubes, uterus
etc.), thus making the foetus
differentiate as a male.
Germinal cells or spermatogonia, which divide by meiosis to form sperm cells
Sertoli cells that support and nourish the developing sperm, secrete testicular
fluid into the tubules, and separate the developing sperm from the bloodstream
(to avoid an autoimmune reaction developing, and to prevent blood-borne toxins
damaging the sperm).
The seminiferous tubules are held in separate ‘compartments’ within each testis,
each of which is surrounded by connective tissue, blood vessels, and clusters of
testosterone-secreting Leydig cells.
Once formed, the spermatozoa are emptied into the main duct of the testis, the
vas deferens, via the long coiled duct known as the epididymis.
The epididymis
The epididymis is a narrow tightly-coiled tube attached to the top of each testis
within the scrotum. The sperm pass through this long tube to reach the vas deferens,
which emerges from the lower section (tail) of the epididymis. During their journey
along the epididymis the sperm mature and develop their motility and their ability to
fertilise an egg.
The vas (ductus) deferens
glossary
Germinal cells: An embryonic
cell that divides to form
gametes.
Spermatogonia: Primitive
male germ cell that gives rise
to primary spermatocytes in
spermatogenesis.
Sertoli cells: Elongated striated
cells in the seminiferous
tubules of the testis to
which the spermatids become
attached and from which they
derive nourishment.
The vas deferens is a long tube continuing from the epididymis, out through the
scrotum and into the abdomen. Here, it passes behind the urinary bladder and
expands to form an ampulla. Each ampulla joins with a seminal vesicle to form
an ejaculatory duct. The vas deferens carries the sperm from the testis to the
ejaculatory ducts during the emission phase of ejaculation. Its walls contain three
layers of smooth muscle innervated by sympathetic nerves. Stimulation of these
nerves propels sperm into the ejaculatory ducts, where sperm and secretions from
the seminal vesicles are stored. The ejaculatory ducts then pass through the prostate
gland (see below), where they receive more secretions, before joining with the single
urethra, the tube through which sperm and urine pass out of the body, via the penis.
Vas deferens: Sperm-carrying
duct, which begins at and is
continuous with the tail of
the epididymis, runs in the
spermatic cord through the
inguinal canal, and descends
into the pelvis where it joins
the duct of the seminal vesicle
to form the ejaculatory duct.
Module 1: Reproduction
The prostate and seminal vesicle
The prostate gland (an accessory sex gland in the male that opens into the urethra
just below the bladder and vas deferens), seminal vesicles and bulbo-urethral
gland all add alkaline secretions to the spermatozoa at ejaculation. These
secretions form the bulk of the semen (the fluid ejaculated from the penis), which
carries the spermatozoa through – and protects them from – the acidic environment
of the vagina.
Penis
The penis deposits semen into the vagina during sexual intercourse and carries urine
through the urethra during urination. Its corpus spongiosum is a ventral cylinder
that carries the urethra and expands to form the glans at the tip of the penis;
its two corpora cavernosa are large cylinders forming the upper surface and sides of
the penis.
Erection of the penis is mediated by dilation of its arteries, controlled by the
parasympathetic nervous system. The spongy spaces (sinuses) within the corpora
become filled with blood at high (arterial) pressure; this rise in blood pressure
collapses the thin veins in the penis, preventing blood from leaving and resulting
in an erection.
glossary
Epididymis: A narrow tightlycoiled tube connecting the
efferent ducts from the rear of
each testicle to its vas deferns.
Urethra: The canal through
which sperm and urine pass out
of the body.
Semen: The reproductive fluid
ejaculated from the penis
consisting of spermatozoa
suspended in secretions of
accessory glands.
Corpus spongiosum: The
longitudinal column of erectile
tissue of the penis that contains
the urethra and is ventral to
the two corpora cavernosa.
Corpora cavernosa: A mass
of erectile tissue with large
interspaces capable of being
distended with blood.
Production of sperm cells – spermatogenesis
As with the formation of sex cells – oocytes – in the female, the formation of sperm
cells – spermatozoa – in the male begins before birth. Sperm cell production, or
spermatogenesis, occurs in the seminiferous tubules.7
1. S tem cells, called spermatogonia, line the seminiferous tubules at birth and contain
the full complement of 46 chromosomes (23 pairs). After birth these
cells continue to divide, with each cell producing two daughter cells with the same
number of chromosomes. At puberty some spermatozoa grow to become primary
spermatocytes.
2. S permatocytes mature through several stages and then undergo meiotic cell division
that reduces the number of chromosomes in the nucleus from 46 to 23.
nice to know
Continuous fertility7
Post-pubertal males are
normally constantly fertile,
although fertility may
decline with age. This is
because there is a constantly
developing population of
stem cells inside the testis
(unlike the finite number of
ova in the ovary):
• A new cycle of
spermatogenesis starts
every 16 days at different
points in the seminiferous
tubule, so cycles are
at different stages in
different segments of
the tubule
• Sertoli cells are arranged
in bands in which cycles
of spermatogenesis begin
at different times.
3. E ach primary spermatocyte produces two secondary spermatocytes from its first
cell division; each secondary spermatocyte undergoes the second meiotic division to
produce two spermatids.
4. Each spermatid develops into a fully mature spermatozoon.
5. T he spermatozoa are released from the seminiferous tubules and take 5–11 days to
travel through the epididymis, where maturation continues. From spermatogonium to
mature sperm cell takes around 64 days.
The process is controlled by the male Y chromosome and, unlike egg development in the
female, is a continuous (not monthly) process.
Spermatogenesis in the microstructure of the seminiferous tubule7
Basement Spermatogonia Spermatid Spermatozoon Spermatocyte
membrane
Lumen
Capillary
Sertoli cell
Interstitial
Leydig cells
Module 1: Reproduction
Seminiferous tubule
Mature spermatozoa are stored in the tail of the epididymis (within the scrotum)
until ejaculation, but only become fully functional when they enter the female
reproductive tract. Storing the spermatozoa within the scrotum keeps them at the
cooler temperature they need to remain in optimum condition for fertilising the egg.
The structure of the sperm cell
Mature spermatozoa have a distinct head and tail. The head is made up largely
of the pointed nucleus, which contains the cell’s genetic material. It has an
acrosomal cap, which is a large vesicle containing enzymes that break down the
wall of the egg during fertilisation.
The middle section of the sperm is packed with mitochondria, cell structures that
are the site of energy production. The tail of the sperm is a specialised flagellum
used for propelling the cell during its journey to the ovum. The main part of the
tail makes up 2/3 of the length of the spermatozoon.
Structure of a spermatozoon7
Head (5 µm long) flattened
and pointed
Neck
Middle piece (7 µm long)
Acrosomal cap (contains
hydrolytic enzymes)
Nucleus (haploid number
of chromosomes)
Spiral mitochondria
Fibrous sheath
Principal piece
of tail (40 µm long)
Fibres
Axoneme
(core of flagellum)
End piece of tail
(5-10 µm long)
glossary
Acrosomal cap: Cap-like
structure that develops over
the anterior half of the head in
the spermatozoa; it contains
enzymes that break down
the wall of the egg during
fertilisation.
Mitochondria: Round or long
cellular organelles that are
found outside the nucleus; rich
in fats, proteins, and enzymes,
they produce energy for the cell
through cellular respiration.
Hormonal control of male reproduction
After puberty (between the ages of 10 and 15), GnRH, LH and FSH control male
reproductive function. As in the female, GnRH released from the hypothalamus
stimulates the pituitary to secrete LH and FSH:
LH causes the Leydig cells of the testes to produce and secrete testosterone
FSH acts on the Sertoli cells, stimulating spermatogenesis by increasing
these cells’ production of androgen receptors and androgen-binding protein.
Androgen-binding protein binds the testosterone needed within the
seminiferous tubules for spermatogenesis.
FSH also stimulates the development of LH receptors on Leydig cells, enabling them
to respond to LH and synthesise androgens. These effects of LH and FSH parallel
the action of these two gonadotropins on the follicular (thecal and granulosa) cells,
described above.
In the next module we look at what can go wrong in the female (and the male)
reproductive systems, leading to reduced fertility for a couple.
Module 1: Reproduction
Glossary
2-cell, two-gonadotropin model: Theory that both thecal and granulosa cells
(2 follicular cell types) and LH and FSH (2 gonadotropins) are needed for full ovarian
stimulation
Acrosomal cap: Cap-like structure that develops over the anterior half of the
head in the spermatozoa; it contains enzymes that break down the wall of the egg
during fertilisation
Ampulla: The middle portion of the fallopian tube
Androgens: Generic term for male hormones (e.g., androsterone, testosterone)
Anti-Müllerian hormone (AMH): A member of the transforming growth factor β
family of growth and differentiation factors. In the ovary, AMH has an inhibitory
effect on primordial follicle recruitment as well as on the responsiveness of growing
follicles to follicle-stimulating hormone (FSH)
Blastocyst: An early stage of development of the embryo shortly after fertilisation;
the stage when it moves into the uterus for implantation
Blastomeres: type of cell produced by division of the egg after fertilisation
Cervix: Lower, narrow portion of the uterus that opens into the top end of
the vagina
Chorion: Highly vascular outer membrane that surrounds the embryo
Corpora cavernosa: A mass of erectile tissue with large interspaces capable of
being distended with blood
Corpus luteum: The ‘yellow body’ formed from the ruptured follicle after ovulation;
composed of remaining granulosa cells that are transformed into luteal cells by the
action of LH
Corpus spongiosum: The longitudinal column of erectile tissue of the penis that
contains the urethra and is ventral to the two corpora cavernosa
Diploid: Cells with two copies of each chromosome, usually one from the mother
and one from the father; human diploid cells have 46 chromosomes
Embryo: An egg that has been fertilised by a sperm and has undergone one or
more cell divisions
Embryoblast: The mass of cells inside the primordial embryo that will eventually
give rise to the definitive structures of the fetus
Endometrium: The mucous membrane lining the uterus that plays a vital role in
nourishing and supporting the developing embryo
Epididymis: A narrow tightly-coiled tube connecting the efferent ducts from the
rear of each testicle to its vas deferns.
Fallopian tubes: A pair of slender ducts through which eggs pass from the ovaries
to the uterus
Fertilisation: The penetration of an egg by the sperm and the resulting combining
of genetic material that develops into an embryo
Fertility: Normal fertility is the ability to achieve a pregnancy within two years by
regular coital exposure
Fimbriae: Fringe of tissue at the ovarian end of the fallopian tube which catches
the newly released egg and sweeps it into the fallopian tube
Follicle: A fluid-filled sac located just beneath the surface of the ovary. It contains
an oocyte and cells that produce hormones. The follicle increases greatly in size and
volume before ovulation, at which time it matures and ruptures to release the egg
Follicle-stimulating hormone (FSH): The pituitary hormone responsible for
stimulating follicle growth and egg development as well as production of
oestrogen in women. In men, FSH helps stimulate the testes to manufacture sperm
Gamete: The mature reproductive or germ cell – an egg or ovum in the female,
and sperm in the male. Each gamete contains half the total number of chromosomes
– i.e. only 23 chromosomes, instead of the 23 pairs of chromosomes (i.e. 46 in total)
found in all the other cells of the body
Germinal cells: An embryonic cell that divides to form gametes
Gonadotropin-releasing hormone (GnRH): Hormone produced by the hypothalamus
that stimulates the pituitary to release gonadotropins (luteinising hormone and
follicle-stimulating hormone)
Gonads: The organs that produce gametes – the testes in males and the ovaries
in females
Granulosa cells: FSH-sensitive cells surrounding the oocyte; those of the dominant
follicle convert androgens to estrogens under the influence of FSH
Human chorionic gonadotropin (hCG): Hormone made by the developing embryo
soon after conception and later by placenta. Its role is to prevent the disintegration
of the corpus luteum of the ovary and thereby maintain progesterone production,
critical for pregnancy
Hyperprolactinaemia: Abnormally high levels of prolactin in the blood
Hypothalamus: Part of the brain above the pituitary that regulates many bodily
functions, including hormone release by the pituitary; integrates incoming hormonal
and nervous signals and secretes releasing-hormones in response
Hypothalamic–pituitary–gonadal axis: A term used to describe the effects of the
hypothalamus, pituitary gland, and gonads as if acting as a single entity – it is
important in the development and regulation of a number of vital body systems,
including development and reproduction
Infertility: Those couples who do not achieve a pregnancy within two years of
regular sexual activity. This group is made up of those defined as sterile or subfertile
Inhibin B: A glycoprotein hormone that is secreted by the pituitary gland and
inhibits the secretion of follicle-stimulating hormone – in the male it is secreted
by the Sertoli cells and in the female by the granulosa cells
Leydig cell: A cell of interstitial tissue of the testis that is usually considered the
chief source of testicular androgens and especially testosterone
Luteinising hormone (LH): The hormone that triggers ovulation and stimulates
the corpus luteum to secrete progesterone
Module 1: Reproduction
Mitochondria: Round or long cellular organelles that are found outside the
nucleus; rich in fats, proteins, and enzymes, they produce energy for the cell through
cellular respiration
Mitosis: Process of cell division by which a cell separates the chromosomes in its
cell nucleus into two identical sets in two nuclei
Morula: An embryo at an early stage of embryonic development
Oestradiol 17β (E2): One of the three major oestrogens naturally occurring in
women – it has a key role in reproduction and development
Oestrogen: The naturally occurring female sex steroid hormone produced by the
ovaries and responsible for development of the reproductive organs and secondary
sexual characteristics, as well as for the proliferation of the endometrium
Oocyte: The immature female gamete, i.e. the cell that devlops to form the mature
ovum or egg
Ovaries: Paired oval organs in the female containing thousands of immature egg
cells held within the follicles; site of sex hormone production (by follicles)
Ovulation: The monthly release of an egg from one of the ovaries
Ovum: A female gamete or egg
Pituitary gland: Gland lying at the base of the brain, beneath the hypothalamus,
that secretes many hormones, including the gonadotropins FSH and LH
Progesterone: Naturally occurring female sex steroid hormone primarily responsible
for the transition of the endometrium from its proliferative to its secretory stage,
regulating fertility
Progestogen: Synthetic steroid hormone similar in structure to the naturally
occurring female sex hormone progesterone
Prolactin: A protein hormone made in the pituitary, it is secreted in large amounts
when the links between the pituitary and hypothalamus are disconnected, therefore
regulation of secretion is maintained by inhibition
Scrotum: The external sac that contains the testes
Semen: The reproductive fluid ejaculated from the penis consisting of spermatozoa
suspended in secretions of accessory glands
Seminiferous tubules: Coiled threadlike tubules that make up the bulk of the
testis and are lined with a layer of epithelial cells from which the spermatozoa
are produced
Spermatogonia: Primitive male germ cell that gives rise to primary spermatocytes
in spermatogenesis
Spermatozoon: A motile male gamete usually with rounded or elongated head and
a long posterior flagellum – it joins with an ovum to form a zygote
Sertoli cells: Elongated striated cells in the seminiferous tubules of the testis to
which the spermatids become attached and from which they derive nourishment
Syncytiotrophoblast: Outer layer of trophoblasts that forms finger-like
projections that invade the endometrium to secure the blastocyst firmly in
place within the uterus
Testosterone: Male hormone produced primarily by the testes that is the
main androgen responsible for inducing and maintaining male secondary
sex characteristics
Theca cells: LH-sensitive cells surrounding the outside of the follicle; those of the
dominant follicle convert cholesterol to androgens under the influence of LH
Trophoblast: The outer layer of the blastocyst that supplies nutrition to the embryo,
facilitates implantation by eroding away the tissues of the uterus with which it
comes in contact allowing the blastocyst to sink into the cavity formed in the
uterine wall
Urethra: The canal through which sperm and urine pass out of the body
Uterus: Hollow, pear-shaped reproductive organ found in the low central region of
the woman’s pelvis; it is in the uterus where the fetus develops during gestation
Vas deferens: Sperm-carrying duct, which begins at and is continuous with the
tail of the epididymis, runs in the spermatic cord through the inguinal canal, and
descends into the pelvis where it joins the duct of the seminal vesicle to form the
ejaculatory duct
Zygote: a cell formed by the union of two gametes
Module 1: Reproduction
References
1. Internal Genital Organs. In: Porter RS, Kaplan JL, Homeier BP, editors. The Merck
Manual Home Health Handbook. http://www.merckmanuals.com/home/index.
html: Merck Sharp & Dohme Corp; 2007.
2. Johnson MH. Essential Reproduction. Sixth ed. Johnson MH, Everitt BJ, editors:
Blackwell Publishing; 2007.
3. Drummond AE. The role of steroids in follicular growth. Reprod Biol Endocrinol.
2006;4:16.
4. Levy DP, Navarro JM, Schattman GL, Davis OK, Rosenwaks Z. The role of LH in
ovarian stimulation: exogenous LH: let’s design the future. Hum Reprod. 2000
Nov;15(11):2258-65.
5. Filicori M, Cognigni GE, Samara A, Melappioni S, Perri T, Cantelli B, et al.
The use of LH activity to drive folliculogenesis: exploring uncharted territories
in ovulation induction. Hum Reprod Update. 2002 Nov-Dec;8(6):543-57.
6. Khan-Sabir N, Beshay VE, Carr BR. Chapter 3: The Normal Menstrual Cycle and the
Control of Ovulation. In: Rebar RW, editor. Female Reproductive Endocrinology:
http://www.endotext.org/; 2008.
7. Sanders S, Debuse M. Endocrine and Reproductive Systems. Second ed.
Horton-Szar D, editor: Mosby; 2003.