The Normal Menstrual cycle L1&2
Introduction :The external manifestation of a normal menstrual cycle is the presence
of regular vaginal bleeding . This occurs as a result of the shedding of
the endometrial lining following failure of fertilizati on of the oocyte or
failure of implantation . The cycle depends on changes occurring within
the ovaries and fluctuation in ovarian hormone levels , that are
themselves controlled by the pituitary and hypothalamus , the
hypothalamo -pituitary -ovarian axis ( HPO ) .
Hypothalamus :The hypothalamus in the forebrain secretes the peptide hormone
gonadotrophn -releasing hormone ( GnRH ) , which in turn controls
pituitary hormone secretion . GnRH must be released in a pulsatile
fashion to stimulate pituitary secr etion of luteinizing hormone ( LH ) and
follicle stimulating hormone ( FSH ) . If GnRH is giving in a constant
high dose , it desensitizes the GnRH receptor and reduces LH and FSH
Clinical view :Drugs that are GnRH agonists ( e.g. buserel in and goserelin ) .
Although they mimic the GnRH hormone , when administered
continuously , they will downregulate the pituitary and consequently
decrease LH and FSH secretion . This has effects on ovarian function
such that oestrogen and progesterone lev els also fall . These preparations
are used as treatments for endometriosis and to shrink fibroids prior
Pituitary glandGnRH stimulation of the basophil cells in the anterior pituitary gland
causes synthesis and release of the gonadotroph ic hormones , FSH and
LH . This process is modulated by the ovarian sex steroid hormones
oestrogen and progesterone ( see Figure 1 ) . Low levels of oestrogen
have an inhibitory effect on LH production ( negative feedback ) ,
whereas high levels of oestrog en will increase LH production ( positive
feedback ) . The mechanism of action for the positive feedback effect of
oestrogen involves an increase in GnRH receptor concentrations , while
the mechanism of the negative feedback effect is uncertain .
The high levels of circulating oestrogen in the late follicular phase of
the ovary act via the positive feedback mechanism to generate a
periovulatory LH surge from the pituitary .
The clinical relevance of these mechanisms is seen in the use of the
combi ned oral contraceptive pill , which artificially creates a constant
serum oestrogen level in the negative feedback range , inducing a
correspondingly low level of gonadotriphin hormone release .
Figure (1) Hyothalamo -pituitary -ovarian axis .Unlike oestrogen , low levels of progresterone have a positive
feedback effect on pituitary LH and FSH secretion ( as seen immediately
prior to ovulation ) and contribute to the FSH surge . High levels of
progesterone , as seen in the luteal phase , inhibit pituitary LH and FSH
production . Positive feedback effects of preogesterone occur via
increasing sensitivity to GnRH in the pituitary . Negative feedback
effects are generated through both decreased GnRH production from the
hypothalamus and decre ased sensitivity to GnRH in the pituitary . It is
known that progesterone can only have these effects on gonadotropic
hormone release after priming by oestrogen ( Figure 2 ) .
There are other hormones which are involved in pituitary
gonadotrophin sec retion . I nhibin i nhibits pituitary FSH secretion ,
whereas activin stimulates it .
OvaryOvaries with developing oocytes are present in the female fetus from
an early stage of development . By the end of the second trimester in
utero , the number o f occytes has reached a maximum and they arrest at
the first prophase step in meiotic division . No new occytes are formed
during the female lifetime . With the onset of menarche , the primordial
follicles containing oocytes will activate and grow in a cyc lical fashion ,
causing ovulation and subsequent menstruation in the event of non -
In the course of a normal menstrual cycle , the ovary will go through
three phases :
1. Follicular phase .
2. Ovulation .
3. Luteal phase .
Follicular phase :The initial stages of follicular development are independent of
hormone stimulation . However , follicular development will fail at the
preantral stage an d follicular atresia will ensue if pituitary hormones LH
and FSH are absent .
FSH levels r ise in the first days of the menstrual cycle , when
oestrogen , progesterone and inhibin levels are low . This stimulates a
co hort of small antral follicles on the ovaries to grow .
Within the follicles , there are two cell types which are involved i n
the processing of steroids , The se are the theca and the granulosa cells ,
which respond to LH and FSH stimulation , respectively . LH
stimulation production of androgens from cholesterol within theca cells .
These androgens are converted into oestrogens by the process of
aromatization in granulose cells , under the influence of FSH . The roles
of FSH and LH in follicular development are demonstrated by studies on
women undergoing ovulation induction in whom endogenous
gonadotrophin production has been su ppressed . If pure FSH alone is
used for ovulation induction , as ovulatory follicle can be produced , but
oestrogen production is markedly reduced . Both FSH and LH are
required to generate a normal cycle with adequate amounts of
As the fo llicles grow and oestrogen secretion increases , there is
negative feedback on the pituitary to decrease FSH secretion . This
assists in the selection of one follicle to continue in its development
towards ovulation – the dominant follicle . In the ovary , the follicle
which has the most efficient aromatase activity and highest
concentration of FSH – induced LH receptors will be the most likely to
survive as FSH levels drop , while smaller follicles will undergo atresia .
The dominant follicle will go on pr oducing oestrogen and also inhibin ,
which enhances androgen synthesis under LH control .
Figure (2) Changes in hormone levels , endometrium and follicle developmentduring the menstrual cycle .
Clinical view :
Administration of exogen ous gonadotrophins is likely to stimulate
growth of multiple follicles which continue to develop and are released
at ovulation ( and can lead to multiple gestations at a rate of around 30
per cent ) .
This situation is used to advantage in patients r equiring in vitro
fertilization ( IVF ) , as many occytes can be harvested from ovaries
which have been stimulated as described above .
There are other au tocrine and paracrine mediators playing a role in the
follicular phase of the menstrual cycle .
These include : Inhibin and activin . Inhibin participates in feedback to
the pituitary to downregulate FSH release , and also appears to enhance
ongoing androgen synthesis . Activin is structurally similar to inhibin ,
but has an opposite action is struct urally similar to inhibin , but has an
opposite action . It is produced in granulosa cells and in the pituitary ,
and acts to increase FSH binding on the follicles .
Insulin -like growth factors ( IGF – I , IGT – II ) act as paracrine
1. In the follicular phase , IGF -I is produced by theca cells under the
action of LH. IGF -I receptors are present on both theca granulosa
cells . Within thec a , IGF -I augments LH -induced st eroidogenesis .
In granulosa cells , IGF -I augments the stimulatory effe cts of FSH
on mitosis , aromatase activity and inhibin production .
2. In the preovulatory follicle , IGF -I enhances LH -induced
progesterone production from granulosa cells .
3. Following ovulation , IGF -II is produced from luteinized
granulosa cells , and act s in an autocrine manner to augment LH -
induced proliferation of granulosa cells .
Kisspeptins are proteins which have more recently been found to play a
role in regulation of the HPO axis , via the mediation of the metabolic
hormone leptin's effect on the hypothalamus , Leptin is thought to be key
in the relationship between energy production , weight and reproductive
health . Mutations in the kisspeptin receptor , gpr -54 , are associated
with delaye d or absent puberty , probably d ue to a reduction in lept in -
liked triggers for gonadotrophin release .
OvulationBy the end of the follicular phase , which lasts an average of 14 days , the
dominant follicle has grown to approximately 20 mm in diameter . As the
follicle matures :
1. FSH induces LH receptor s on the granulosa cells to compensate for
lower FSH levels and prepare for the signal ovulation .
2. Production of oestrogen increases until they reach the necessary
threshold to exert a positive feedback effort on the hypothalamus and
pituitary to cause th e LH surge .
3. This occurs over 24 – 36 hours , during which time the LH -induced
luteinization of granulosa cells in the dominant follicle causes
progesterone to be produced , adding further to the positive feedback
for LH secretion and causing a small peri ovulatory rise in FSH .
4. Androgens , synthesized in the theca cells , also rise around the time of
ovulation and this is thought to have an important role in stimulating
libido , ensuring that sexual activity is likely to occur at the time of
greatest fert ility .
Clinical view :1. The LH surge is one of the best predictors of imminent ovulation , and
this is the hormone detected in urine by most over -the -counter
'ovulation predictor' tests .
2. The LH surge has another function in stimulating the resumption of
meiosis in the occyte just prior to its release . The physical ovulation of
the oocyte occurs after breakdown of the follicular was occurs under
the influence of LH , FSH and progesterone -controlled proteolytic
enzymes , such as plasminogen activators a nd pro taglandins . There
appears to be an inflammatory -type response within the follicle wall
which may assist in extrusion of the oocyte by stimulating smooth
muscle activity .
Thus , women wishing to become pregnant should be advised to avoid
taking pro staglandin synthetase inhibitors .
Luteal phase :
After the release of the oocyte , the remaining granulosa and theca
cells on the ovary form the corpus luteum . The granulosa cells have a
vacuolated appearance with accumulated yellow pigment , henc e the
name corpus luteum ( ' yellow body ' )
On going pituitary LH secretion and granulosa cell activity ensures a
supply of progesterone which stabilizes the endometrium in preparation
for pregnancy . Progesterone levels are at their highest in the cy cle
during the luteal phase . This also has the effect of suppressing FSH and
LH secretion to a level that will not produce further follicular growth in
the ovary during that cycle .
The luteal phase lasts 14 days in most women , without great
variati on . In the absence of beta human chorionic ganadotrophin
( BHCG ) being produced from an implanting embryo , the corpus
luteum will regress in a process known as luteolysis .
The withdrawal of progesterone has the effect on the uterus of causing
shed ding of the endometrium and thus menstruation . Reduction in
levels of progesterone , oestrogen and inhibin feeding back to the
pituitary cause increased secretion of gonadotrophic hormone ,
particularly FSH . New preantral follicles begin to be stimulated and the
cycle begin s a new .
Endometrium :The specific secondary changes in the uterine endometrium give the
most obvious external sign of regular cycles .
Menstruation :The endometrium is under the influence of sex steroids that circulat e
in females of reproductive age .
During the ovarian follicular phase , the endometrium undergoes
profileration ( the ' proliferative phase ' ) ; during the ovarian luteal
phase , it has its ' secretory phase ' , Decidualization , the formation of a
specialized glandular endometrim , is an irreversible process and
apoptosis occurs if there is no embryo implantation . Menstruation
(day 1) is the shedding of the 'dead' endometrium and ceases as the
endometrium regenerates ( which normally happens b y day 5 – 6 of the
cycle ) .
The endometrium is composed of two layers , the uppermost of which
is shed during menstruation . A fall in circulating levels of oestrogen and
progesterone approximately 14 days after ovulation leads to loss of
tissue flui d , vasoconstriction of spiral arterioles and distal ischaemia .
This results in tissue breakdown , and loss of the upper layer along with
bleeding from fragments of the remaining arterioles is seen as menstrual
bleeding . Enhanced fibrinolysis reduces clo tting .
Clinical view :1. The effects of oestrogen and progesterone on the endometrium can
be reproduced artificially , for example in patients taking the
combined oral contraceptive pill or hormone replacement therapy
who experience a withdrawal bleed du ring their pill -free week
each month . Vaginal bleeding will cease after 5 – 10 days as
arterioles vasconstrict and the endometrium begins to regenerate .
2. In rare cases , the tissue breakdown and vasoconstriction does not occur
correctly and the endometri um may develop scarring which goes on to
inhibit its function . This is known as ' Asherman's syndrome ' . The
endocrine influences in menstruation are clear . However there is also
paracrine mediators influence in menstruation , include : prostaglandin
F2 a , endothelin -1 and platelet activating factor ( PAF ) are
vasoconstrictors which are produced within the endometrium . They
may be balanced by the effect of vasodilator agents , such as
prostaglandin E 2 , prostacyclin ( PGI ) and nitric oxide (NO) , whic h
are also produced by the endometrium .
3. Recent research has shown that progesterone withdrawal increases
endometrial prostaglandin ( PG ) synthesis and decreases PG
metabolism . The COX -2 enzyme and chemokines are involved in PG
synthesis and this is lik ely to be the target of non -steroidal anti -
inflammatory agents used for the treatment of heavy and painful
The proliferative phase :
Once endometrial repair is complete . After this time , the endometrium
enters the proliferative phase , when glandular and stromal growth occur . The
epithelium lining the endometrial glands changes from a single layer of
columnar cells to a pseudostratified epithelium with frequent mitoses .
Endometrial thickness increases rapidly , from 0.5 mm at men struation to
3.5 – 5 mm at the end of the proliferative phase .
Figure (3) Tissue sections of normal endometrium during proilferative andsecretory phases of the menstrual cycle .
The secretory phaseAfter ovulation ( generally around day 14 ) , there is a period of
endometrial glandular secretory activity . following the progesterone
surge , the oestrogen -induced cellular proliferation is inhibited and the
endometrial thickness does not increase any further . However , the
endometrial glands will become more tortuous , spiral arteries will
grow , and fluid is secreted into glandular cells and into the uterine
lumen . Later in the secretory phase , progesterone induces the formation
of a temporary layer , known as the decidua . Stromal c ells show
increased mitotic activity , nuclear enlargement and generation of a
basement membrane .
Recent research into infertility has identified apical membrane
projections of the endometrial epithelial cells known as pinopodes ,
which appear after day 21 -22 and appear to be a progesterone -dependent
stage in making the endmetrium receptive for embryo implantation
( Figure 4 ) .
Figure (4) photomicrograph of endometrial pinopodes from the implantationwindow .
Immediately prior to me nstruation , three distinct layers ofendometrium can be seen .
1. The basalis is the lower 25 per cent of the endomtrium , which will
remain throughout menstruation and shows few changes during the
menstrual cycle .
2. The mid -portion is the stratum spongi osu m with oedematous
stroma and exhausted glands .
3. The superficial portion ( upper 25 per cent ) is the stratum
compactum with prominent decidualized stromal cells . On the
withdrawal of both oestrogen and progesterone , the decidua will
collapse , with vaso constriction and relaxation of spiral arteries
and shedding of the outer layers of the endometrium .
New developments :
Measurement of ovarian reserve :
Female reproductive potential is directly proportionate to the
remaining number of ooc ytes in the ovaries . This number decreases
from birth onwards .
It is desirable to be able to quantify the residual ovarian capacity of
women of older age or after undergoing treatment in order to give
prognostic information and management advice t o patients , and also to
compare different forms of treatment . Research using :
1. Altrasound markers has looked at measurements of ovarian
volume , mean ovarian diameter and antral follicle count to
calculate ovarian reserve .
2. Biochemical markers include FSH . oestrodiol , inhibin B , anti -
Mullerian hormone ( AMH ) . AMH is produced in the granulosa
cells of ovarian follicles and does not change in response to
gonadotrophins during the menstrual cycle . As a result , it can be
measured and compared from an y point in the cycle .
Harvesting ovarian tissue :Harvesting and cryopreservation of ovarian tissue is an emerging
technique in reproductive biology . At present , its use is experimental and
offered to nulliparious women or young females undergoi ng gonadotrophic
therapy , for example to treat cancer . The theory is that strips of ovarian
cortex can be removed at laparoscopy or laparotomy and preserved by
freezing , in the hope that future technology will allow them to be thawed and
used to generat e occytes for IVF treatment .
It is important to have an understanding of the physiology of thenormal menstrual cycle to understand the causes of any abnormalities ,
and also to tackle problems , such as infertility and the preve ntion of
unwanted pregnancy . This lecture aims to describe the mechanisms
involved in the normal menstrual cycle , with emphasis on the clinical
relevance of each phase .