An introduction to

Reproductive Physiology

Dr.ZAINAL ARIFIN,SpOG
Reproductive Immunoendocrinology Division
Department of Obstetric and Gynecology
RSCM-FKUI, Jakarta

The effect of sex steroid :

Determinative
Involve essentially qualitative
changes, which are irreversible
or only partially reversible

Regulatory
Are reversible, and can involve
both quantitative and
qualitative changes to
established accessory sex
organs and tissues
They are concerned with
ensuring that their reproductive
tracts and genitalia function
effectively in the reproductive
process
It is regulatory of E and P that
results in the external
manifestations of the
menstrual and oestrous cycle.
These external changes are
accompanied by cyclic
changes in the vagina, cervix,
uterus and oviducts

E and P affect gamete

transport by actions on the
oviduct

Thin muscular tube, covered

externally with serosal tissue
and peritoneum, and ciliated,
secretory, high columnar
epithelium overlies the stromal
tissue internally.
The site of fertilization and
therefore the oocyte passes
along it from the fimbriated
ostium towards the
spermatozoa
Must provide a suitable
environment for fertilization and
the early growth of the
conceptus

Effect of E : maintain ciliated, high collumnar epithelium and secretory activity

Effect of P : the numbers of cilia decline, and the quantity of the oviducal secretion
also decline, the small volume of fluid having a low sugar and protein content. May
also exert a mildly depressant effect on oviducal musculature, particularly relaxing
the spinchter-like muscle at the utero-tubal junction

The ratio changes between E

and P will influenced the
gamete and conceptus transport

If administered highly dose of

exogenous estrogen within 72
hours of fertilization will cause
an early expulsion of the
conceptus from the oviduct via
uterus into the vagina
If it administered earlier, then it
can prevent the passage of the
conceptus to the uterus by
causing prolonged spasm of the
oviductal musculature which can
cause tubal blocking

E and P cause cyclic changes

in the uterus to support
gamete transport and
implantation

There is a cyclical changes in

structure and function
First, the uterus will prepares to
receive and transport the
spermatozoa from the cervix to
the oviduct
Second, the uterus prepares to
receive the conceptus from the
oviduct and and norish it

Follicular / Proliferation
phase

Is the period during which

estrogen rise rapidly
The myometrium increase both
its contractility and its excitability
The endometrium shows
stromal thickening, partly due to
stromal cell proliferation and
partly due to stromal oedema
The surface epithelium increase
in surface area and metabolic
activity
The estrogen primed epithelial
cells secrete a fluid characteristically watery constitutions which
contains a range of proteins
including proteolytic enzymes

Luteal / Secretory Phase

After the estrogen surge and

ovulation have occurred, the
uterus is primed to bind
progesterone
Progesterone stimulate the
synthesis of secretory materials
by the glands so they become
distended with a thick secretion
rich in glycoprotein, sugars and
amino acids
Stromal cells become larger and
plumper
Characteristics spiral arteries
become fully developed
The excitability of the uterine
muscle become depressed
Progesterone action will only
occur in the estrogen primed
uterus

The cervix shows cyclical

changes which affect gamete
transport

Traversed by spermatozoa during

coitus and the neonate during
parturition
The spematozoa must actively
swim through the cervix
During follicular phase the muscle
of the cervix relax and the
epithelium become secretory
During luteal phase secretion is
reduced and the cervix is firmer
E enhance sperm penetration while
P depresses penetration
Sperm penetration low at the luteal
phase and become maximum at
the time of ovulation

Cervical
mucus

The steroids act via an effect on

the amount and nature of the
glycoproteins secreted by the
cervical epithelium
Under P dominance, small
volumes of thick mucus are
secreted and strands of mucus
can only be stretched a short
length before the threads snap :
a low spinnbarkeit
If mucus from E cervices is
allowed to dry on a slide, its
distinctive molecular
composition results in a
characteristics pattern know as
ferning

E and P cause cyclic

structural changes in the
vagina

E induce an increased mitotic

activity in the columnar
epithelium of the vagina, with a
tendency to keratinize
The fluids within the vagina also
change during the cycle, and
one effect of this is to vary the
metabolic substrates available
to the bacterial flora there

The transport of spermatozoa to the

oocyte is hazardous and most do not
arrive
The spermatozoa must travel

through the male and female

genital tract which more than
100.000 times of their own
length to reach the oviduct
(30 40 cm)
Fewer than one in a million of
the spermatozoa produced ever
complete the journey because :
The journey is difficult
The spermatozoa must
successfully undergo a series
of changes in both the male
and female genital tracts before
they gain full fertilizing capacity

Male Reproductive System Sperm Production

Sperm is produced in the testes, in the

Seminiferous tubules.
Seminiferous tubules are made up of
two classes of cells
1) Germ cells - make the sperm
2) Sertoli cells - supporting cells
Leydig cells - interstitial cells in the
space between tubules. They produce
testosterone
Decrease in blood testosterone levels
stimulates GnRH release from the
hypothalamus
GnRH promotes release of FSH and LH
from the anterior pituitary
FSH binds to receptors on Sertoli cells.
Activation of Sertoli Cells stimulates
spermatogenesis in germ cells.

Spermatozoa require a
period of epididymal
maturation
Spermatozoa release to the rete

testis from the sertoli cells by

fluid flow which produced by
sertoli cells
As the fluid passes through the
rete testis the composition of its
ions and smal molecules
changes
The spermatozoa are then
carried into the epididymis
through the vasa efferentia

Epididymal maturation

Most of the fluid is reabsorbed,

concentrating the spermatozoa 100fold
This absorption depends upon the
action of E on epididymis
Spermatozoa become dependent on
the activity of epididymal musculature
on their onward movement
Adds secretory products including
carnitine, glycerophos-phorylcholine,
fructose and glycoproteins (coating the
surface of spermatozoa)
Passage through the vasa efferentia
and epididymis takes around 6-12
days
By the time they arrive at the cauda,
spermatozoa have acquired the
potential to fertilize oocytes and to
swim progressively

Epididymal maturation

Besides functional capability maturation

process also accompanied by changes
in the biochemistry and morphology of
the spermatozoa
The whole process of maturations is
crucially dependent upon adequate
stimulation of the epididymis by
androgens
The androgen which stimulate the
epididymis was derived from the lymph
and the fluid entering from the vasa
efferentia, not from the circulation
(synthesis by itself ???)
Spermatozoa will be storage for only for
a few days in the cauda
Spermatozoa enter the vas deferens as
a very densely packed mass, and their
transport is no longer a result of fluid
movement but due to the muscular
activity of the epididymis and vas
deferens

Semen is made up of
spermatozoa and seminal plasma

Ejaculated spermatozoa are carried to

the female tract in seminal plasma
Seminal plasma is derived largely from
the major accessory sex glands
Seminal fluid is not essential for the
spermatozoa function, but it was
require for transportation, and also
provides nutrition (fructose, sorbitol),
buffering capacity and reducing agents
to protect against oxidation following
exposure to atmospheric oxygen
Prostaglandin in semen might
stimulate muscular activity in the
female tract
Semen doesnt only carry
spermatozoa and substances to assist
the maintenance of sperm fertility but
also a large number of leucocytes and
potential infective agents

Semen is deposited in the

vagina

The semen is ejaculated within the vagina and onto the cervical
os
The semen coagulates rapidly during or immediately after
deposition and the coagulation will become gelatinous
Coagulating enzymes derived from the prostate interact with a
fibrinogen-like substrate derived from the seminal vesicle
The coagulum may act to retain spermatozoa in the vagina
preventing their physical loss or perhaps buffering them against
the hostile acidity of the vaginal fluid (pH 5.7)
The coagulum is dissolved within 20-60 minutes by progressive
activation of a proenzyme derived from the prostatic secretion of
the ejaculate

Spermatozoa are transported

largely by their own
activity

The ciliated surface of the cervical

os wafts them toward the cervical
canal
Over 99% of spermatozoa do not
enter the cervix and are lost by
leakage from the vagina
The few successful spermatozoa
may survive for many hours deep
in the cervical crypts of the
mucous membrane and they also
nourished by mucoid secretion
Only in the absence of P
domination does the mucus permit
sperm penetration

The vagina, cervical and uterine

movements often present in the
preorgasmic and orgasmic phases
are not required for effective sperm
transport, but may assist it
The spermatozoa probably move
through the uterus and into the
ampulla of the oviduct by their own
propulsion and in currents of fluid
set up by the action of uterine cilia
The cervical crypts may act as a
reservoir slowly releasing sperm into
the uterus, and the uterotubal
junction seems to regulate entry to
the oviduct by its action as an
intermittent spinchter
After reach the isthmus the
spermatozoa tend to linger and
immotile, but only at ovulation do
spermatozoa re-acquire motility and
swim to the ampullary-isthmic
junction and the site of potential
fertilization
The oocyte-cumulus mass might
produce a chemotactic factor

Oocyte transport depends on

the activity of the oviduct

The ovulated oocytes is picked

up from the surface of the ovary
in the peritoneal cavity by the
fimbriated ostium of the oviduct
and swept by oviducal cilia
along the ampulla towards the
junctionwith the isthmus
Oocyte transport is affected
adversely if cumulus cells are
lacking and or if oviducal cilia
are malfunctional

Spermatozoa gain their full

fertilizing capacity in the female
tract
This attainment of a full fertilizing
capacity within the female tract is
called capacitation
Process : stripping from the
spermatozoal surface of the coating
of glycoprotein molecules acquired
during passage through the
epididymis and after contact with the
seminal plasma
The process is reversible
An estrogen primed uterus or
oviducal isthmus is optimal for
capacitation
(1) change in the movement
characteristics : hyperactivity motility
pattern, (2) change in the surface
membrane

The acrosome
reaction

After undergo capacitation

reaction than the spermatozoa
can also undergo the acrosome
reaction which essential before
spermatozoa bind and penetrate
the zona pelucida
The acrosome swells, its
membrane fuses with the
overlying plasma membrane, a
vesiculated appearance is
created and the contents of the
acrosomal vesicle and the inner
acrosomal membrane both
become exteriorized
The calcium elevation and rising
in intracellular pH may work
synergistically

The role of
progesterone

Progesterone can also stimulate an

influx of calcium into spermatozoa
The follicular production of
progesterone rises just prior to
ovulation and it is possible that
progesterone is carried in the cumulus
mass of granulosa cells surrounding
the oocyte
In vivo progesterone will cause release
of intra-acrosomal enzyme
hyaluronidase which can digest the
intercellular matrix of hyaluronic acid
which holds together the cumulus cells
around the oocyte
It will facilitating the passage of
spermatozoa through the cumulus
towards the zona pellucida, the
interaction with ZP3 and the definitive
acrosome reaction

The acrosome
reaction

The agent which responsible

for the acrosome reaction is
a constituent of the zona
pellucida callled ZP3
The sperm binding site is
located on the plasma
membrane overlying the
acrosome (1,4-galactosyl
transferase) which will bound
to ZP3 glycoprotein, then
interact with the sperm
plasma membrane and via
action involving a G protein,
stimulate calcium influx and a
rise in pH
Spermatozoal binding to ZP3
is short lived : (1) sperm
receptor for ZP3 is shedding,
(2) b-hexaminidase release
will digest any local ZP3
receptor

The exposure of the inner

acrosomal membrane reveals a
new set of binding sites, this
time specific for a ZP2
These binding sites hold the
spermatozoa and zona in
contact and their action and
their action is essential for the
passage of the spermatozoon
through the zona pellucida
towards the oocyte
It is important that the acrosome
reaction occurs close to the
oocyte, because acrosomereacted spermatozoa have a
very short life span

Spermatozoa who reach the zona with intact acrosome can bind to ZP3 via receptor on
the sperm surface
The ZP3 induces the acrosomal reaction to expose the ZP2 binding sites on the inner
acrosomal membrane and also exposed to proteolytic enzymes which digest a path
through the zona and also aided by the whiplash forward propulsion of the
hyperactivated tail
The spermatozoon now lie tangential to the oocyte at the perivitelline space, where
microvilli on the surface of the oocyte envelop the sperm head
Zona penetration takes between 5 20 minutes

The surface membrane overlying the

middle and the posterior half of the
spermatozoal head (the equatorial and
postacrosomal region) is the site of
fusion with the oolemma
Only capacitated spermatozoa that have
undergone an acrosome reaction are
capable of fusion
The fusion process may involve an
interaction between an integrin-like
molecule in the oolemma and a
disintegrin-ligand on the spermatozoon
Calcium is required for the fusion
process and its action may be mediated
by calmodulin
Once fusion has occurred, the
spermatozoon ceases to move and its
nucleus (together with variable parts of
the midpiece and tail contents) passes
into the ooplasm

Within 1-3 minutes after fusion

process, there is dramatic
increase in the level of free
intracellular calcium in the egg
due largely to the release of
calcium from internal stores
The rise in calcium is
associated with a change in the
pattern of protein phosphorylation in the oocyte
The binding of a sperm to its
receptor is followed by the
activation of an enzyme

Note : TK = tyrosine kinase, PLC = phospholipase C, R+G = G-protein-linked

receptor, PLCb = phospholipase C, IP3 = inositol triphosphate, SF = sperm
cytoplasmic factor

The establishment of diploidy requires a

single fertilizing spermatozoon and the
expulsion of the second polar body

Must prevent polyspermi

The calcium released play a key
role in achieving diploidy,
elevated calcium results :
Cortical reactions (cortical
granules will release their
contents in the perivitelline
space)
The zona reaction (contents of
these granules are enzymes
that act on ZP to prevent or
impair, further binding or
penetration by spermatozoa

Reduction in the sperm-binding

properties of the oolemma itself
(unknown)

Ca2+

The establishment of diploidy requires a

single fertilizing spermatozoon and the
expulsion of the second polar body

Oocyte was ovulated arrested in its

second meiotic division
It must transmit only one set of
chromosomes dispatching one set
of chromosomes to the 2nd polar body
This arrest depends upon the
continuing presence of :

Maturation promoting factor (MPF)

cdk1 and cyclin B
Cytostatic factor (CSF)

Raised calcium destroys cyclin B and

CSF the spindle is no longer
stabilize and meiosis resumed
The extrusion of 2nd polar body also
require the activity of protein kinase C
It takes 30-45 minutes

Spermatozoon contributes
centrosomes consists of
centriole plus pericentriolar
material which have a role in
regulation of karyo and
cytokinesis
Oocytes provides the cell
membrane, cytoplasm, cell
organelles and macromolecular
matrix in which the 2 sets of the
chromosomes and centrosome
operate (maternal cytoplasmic
inheritance)
All the mitochondria in the adult
are maternally derived small
part of the total genetic
inheritance that is exclusively
maternally inherited

Highly condensed chromatin will

become decondensated by
released and replaced the
protamines by histone and its
actively induced by glutathione
2 sets of haploid chromosomes
each become surrounded by
distinct membrane pronuclei
Both of pronuclei will become
more central and adjacent
cytoplasmic position
Syngami : coming together of
the gametic chromosomes
The cleavage furrow forms and
the one cell zygote becomes a
two cell conseptus

Oocytes can be activated in

the absence of a spermatozoon

An oocyte may be activated

parthenogenetically by a variety
of bizarre stimuli (electric shock,
enzyme, alcohol)
Activation by these stimuli is
especially easy in aged oocytes
that have been ovulated several
hours previously
The stimuli induced calcium
rise, thereby mimicking the act
of spermatozoal fusion