Every to cause ovulation. The HPG axisEvery to cause ovulation. The HPG axis

Every
month, the lining of the uterus called the endometrium is shed in a process
called menstruation. Menarche is the first menstrual bleed a female will
experience at an average age of 131. Each menstrual cycle averages
at 28 days but can vary between 21 and 35 days2. Menstrual bleeds typically
occur every month until menopause is reached at an average age of 513.
Menstrual bleeding is a physiological response to when the body prepares the
endometrium of the uterus for the implantation of a blastocyst but recognises
the absence of pregnancy. Irregular menstrual cycles are those that vary by 4 or
more days between one cycle to the next however irregular bleeding patterns may
lead to changes in flow, duration and volume. Both irregular cycles and
bleeding patterns may be associated with abnormalities in uterine function. The
health of the endometrium is highly implicated in the fertility of a woman therefore
over the past few years, the mechanisms underpinning normal menstrual bleeding
and abnormal uterine bleeding have been extensively researched. In particular
the abnormalities in endometrial function that lead to dysfunctional uterine
bleeding will be explored. Dysfunctional uterine bleeding (DUB) is defined as
‘abnormal uterine bleeding in the absence of organic disease’4.

 

Control
of the menstrual cycle

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The
hypothalamic-pituitary-gonadal (HPG) axis plays a pivotal role in menstrual
bleeding. The hypothalamus releases gonadotrophin releasing hormone (GnRH)
which acts on GnRH receptors on gonadotrophic cells of the anterior pituitary.
This stimulates the synthesis and secretion of follicle stimulating hormone (FSH)
and luteinising hormone (LH) which act on the ovaries to stimulate
folliculogenesis and steroidogenesis, particularly oestrogen and progesterone. During
the menstrual cycle, these gonadotrophin hormones are cyclically regulated to
cause ovulation. The HPG axis is quiescent from a few years after birth until
puberty where the factor that initiates reactivation is not completely known.
During the quiescent period, GnRH neurones are restrained from releasing
pulsatile GnRH. As the HPG axis is reactivated, there is a nocturnal rise in
GnRH pulses for approximately a year until a girl undergoes menarche.

 

Folliculogenesis

To
understand the menstrual cycle and the mechanisms that control menstrual
bleeding, it is essential to understand the stages of folliculogenesis. Woman are
born with a reserve of resting primordial follicles. Unidentified intra-ovarian
factors initiate growth of the resting primordial follicles to the pre-antral
stage. This process is gonadotrophin-independent therefore does not require FSH
and LH. The process of growth to the pre-antral stage is occurring all of the
time irrespective of using hormonal contraception or pregnancy. Once the
follicles reach a certain size and want to continue their growth, they need FSH.
When FSH is present, a cohort of follicles is recruited into the menstrual
cycle where from this cohort, one follicle will be selected to be the dominant
follicle which will be ovulated. The processes of follicle recruitment, dominant
follicle selection and ovulation is dependent on the cyclical changes of oestrogen,
progesterone, LH and FSH.

 

Physiology
of the menstrual cycle

Physiologically,
the menstrual cycle refers to the natural changes in ovarian hormones that are
occurring which lead to ovulation of a single, dominant follicle. The cycle can
be divided into the follicular and luteal phases. Day one of the menstrual
cycle is the first day of menstrual bleeding. This is followed by the
follicular phase which is dominated by oestrogen and precedes the luteal phase
which is dominated by progesterone. The follicular phase varies in its length
whereas the luteal phase is fixed at 14 days as this is the lifespan of the
corpus luteum – the remnant of the follicle once the oocyte is ovulated.

 

In the late
luteal and early follicular phase, progesterone declines due to the death of the
corpus luteum. Lowering levels of progesterone feedback to the pituitary which causes
FSH to be selectively raised This inter-cycle rise of FSH in follicles causes
recruitment of the early antral follicles into the menstrual cycle. These
follicles continue to grow and begin to produce oestrogen in the mid-follicular
phase. As oestrogen increases and feeds back to the pituitary, it reinstates
negative feedback to decrease FSH. The fall in FSH allows dominant follicle
selection and death of the rest of the antral follicles to prevent
poly-ovulation.

In the mid
cycle, once there is a sustained amount of high oestrogen for 48 hours, the HPG
axis switches to positive feedback which causes a surge of LH triggering
ovulation. In an average cycle of 28 days, ovulation will occur around day 14.

After
ovulation in the luteal phase, the remaining granulosa and theca cells of the
follicle get remodelled into the corpus luteum which produces progesterone. If
an oocyte is fertilised and starts to produce human chorionic gonadotrophin,
this maintains the corpus luteum. However, when pregnancy is absent, the
progesterone reinstates negative feedback and will override any positive
feedback effects of oestrogen allowing the menstrual cycle to start again.  The falling levels of progesterone leads to menstrual
bleeding.

 

Figure 1
– Physiological changes
in the concentrations of oestrogen, progesterone, LH and FSH during the
menstrual cycle to cause ovulation and menstrual bleeding

 

Physiology
of the uterine cycle

In order to
understand how menstrual bleeding is initiated, it is also important to appreciate
the structural changes that the endometrium undergoes. The physical changes in the
endometrium that correlate with the hormonal changes in oestrogen and
progesterone are described in the uterine cycle which describes how the
endometrium is remodelled to become receptive for implantation. In the
follicular phase, there is a rise in oestrogen. The follicular phase
corresponds with the proliferative phase of the uterine cycle where high levels
of oestrogen causes the endometrium to proliferate and grow in depth to
approximately 15mm. As well as proliferation, oestrogen causes increased blood
flow to the spiral arteries and development of secretory glands.

Once
ovulation has occurred, the levels of progesterone increase in the luteal phase
of the menstrual cycle which is synonymous with the secretory phase of the
uterine cycle. Progesterone stimulates the endometrium to differentiate into
uterine glands and secrete many growth factors, cytokines and adhesion
molecules. This allows the endometrium to become more receptive for the incoming
embryo.  In addition to this,
progesterone stimulates the formation of spiral arteries which temporarily
supply the endometrium with blood during the luteal phase. When progesterone
begins to decline, the spiral arteries begin to coil.

 

Mechanism
of menstrual bleeding

The mechanisms
that control menstrual bleeding are tightly regulated to allow bleeding without
it being excessive. Once oestrogen and the LH surge cause ovulation, the
remnant of the follicle is remodelled into the corpus luteum which produces
high amounts of progesterone which causes the endometrium to become secretory.
When pregnancy is absent, there is death of the corpus luteum in the late
luteal phase after 14 days which causes a decline in progesterone.  This decline prompts the release of
prostaglandins in the endometrium which can act on and influence vascular smooth
muscle. Prostaglandin E2 and prostacyclin I2 are potent vasodilators whereas
prostaglandin F2a causes
spiral arteries to temporarily constrict. In the secretory phase of the uterine
cycle, prostaglandin E2 and I2 cause vasodilatation of the spiral arteries
allowing the endometrium to become richly vascularised. Before menstruation,
the spiral arteries go through episodes of vasoconstriction caused by prostaglandin
F2a. These episodes manifest
symptomatically as abdominal cramps. Vasoconstriction of the spiral arteries
occludes the blood supply to the endometrium and starves it of oxygen. Therefore,
the lack of oxygen in the endometrium causes ischaemia and damage to the spiral
arteries thus leading to necrosis of the tissue. The reduction in progesterone
also affects endometrial lysosomes which release proteolytic and hydrolytic enzymes.
An example of these enzymes are matrix metalloproteinases (MMP) which break
down the stroma of the endometrium. As prostaglandin F2a decreases, there is dilatation of
the spiral arteries leading to a discharged of blood, endometrial tissue and
fibrin clots3. Ultimately, it is apparent that prostaglandins are
the major control factor in menstrual bleeding.

 

What is
Dysfunctional Uterine Bleeding?

Dysfunctional
uterine bleeding accounts for 50% of cases that cause menorrhagia (excessive menstrual
bleeding). Its definition suggests that it is diagnosed based on exclusion of structural
uterine pathologies such as endometrial polyps, fibroids, hyperplasia,
infection or pregnancy which can also be reasons abnormal uterine bleeding. Dysfunctional
uterine bleeding can lead to issues with the frequency, duration and volume of
blood during menstruation thus leading to menorrhagia and polymenorrheoa. Most
commonly, dysfunctional uterine bleeding causes menorrhagia. When diagnosing
DUB, it is of utmost importance that a menstrual cycle history is taken to
establish whether it is regular or irregular. Dysfunctional uterine bleeding
can be classified as either ovulatory or anovulatory therefore determining the
regularity of the cycles would help diagnose the type of DUB. Ovulatory DUB involves
regular menstrual cycles with excessive bleeding during each menstruation.  In contrast to this, anovulatory DUB is characterised
as periods of amenorrhoea followed by menorrhagia when menstruation does occur.
80% of DUB cases are of the ovulatory type. Considering that DUB occurs in the
absence of endometrial pathology, this proposes that it is related to disruptions
in the molecular function of the endometrium or disturbances in hormones that
act on the endometrium.

 

 

Abnormalities
in endometrial function that lead to DUB

As menstrual
bleeding is a balancing act between haemostatic and fibrinolytic events, it is
quite easy for these processes to go wrong. 
Many theories are proposed for the mechanism of dysfunctional uterine
bleeding but it is clear among the literature that it is related to molecular abnormalities
in the endometrium. The endometrium is under very tight regulation by oestrogen
and progesterone which balance its proliferation and shedding. It is thought
that there are two mechanisms which may lead to dysfunctional uterine bleeding
that are dependent on DUB either being ovulatory or anovulatory. Ovulatory DUB
is associated with disturbances mainly related to prostaglandins but also other
molecules which will be further discussed.  Anovulatory DUB is thought to be associated
with dysregulation of the HPG axis.

 

In
anovulatory DUB, dysregulation of the HPG axis can lead to sex steroid levels being
altered. When oestrogen and progesterone are altered, this can lead to periods
of amenorrhoea and anovulation for several months. In anovulatory women, the
corpus luteum does not form and produce progesterone as an oocyte is not
ovulated. This is turn leads to unopposed actions of oestrogen on the
endometrium causing it to continuously proliferate. The absence of progesterone
means that endometrial growth is not stabilised or balanced. Once the oestrogen
decreases or progesterone is produced, the endometrium breaks down unevenly and
excessively resulting in menorrhagia.  

It is also
known that when progesterone limits the growth of the endometrium, there is an
increase in prostaglandin F2a synthesis which triggers uniform shedding of
the endometrium and vasoconstriction to limit blood loss. In women with
anovulatory DUB, it has been shown that abnormal endometrial growth leads to
women having lower levels of arachidonic acid, a precursor of prostaglandins. Consequently,
reduced levels of arachidonic acid may lead to lower levels of prostaglandin F2a thus causing excessive bleeding and
uneven shedding of the endometrium. It is
apparent that the underlying mechanisms that cause anovulatory DUB are not completely understood but there is
strong evidence to suggest that is most likely associated with imbalances in
sex steroids produced in the ovaries.  Abnormal
levels of oestrogen and certain prostaglandins provide a plausible mechanism for
abnormal endometrial function that leads to excessive menstrual bleeding.  

 

In contrast
to anovulatory DUB, ovulatory DUB is not associated with dysregulation of the
HPG axis. Instead, it is thought that there are issues within the mechanisms
that control blood loss itself and therefore is a defect in the haemostatic
processes i.e. coagulation and fibrinolysis. This may involve disruption of
platelet plug formation or fibrinolytic processes where the breakdown of the platelet
plug is abnormally rapid leading to impaired control and excess blood loss
during menstruation. One study in particular showed that the vasodilator prostaglandin
I2 inhibits platelet plug formation and is found at higher levels in the
endometrium of woman with ovulatory DUB thus preventing a platelet plug from
forming and bleeding more. In addition to these defects, it is also shown that
there are other abnormalities in the function of the endometrium related to
inflammation. Considering that ovulation leads to a mild inflammatory reaction
in the ovaries, prostaglandins and immune cells infiltrate the site to quickly
repair the damage. In woman with ovulatory DUB and menorrhagia, it has been
shown that there are is a disproportionate rise in prostaglandin E2 which
causes the spiral arteries supplying the endometrium to vasodilate and could be
a mechanism for the excess bleeding due to increased blood flow to these
vessels.  It is also thought that
menorrhagia can be due to decreased peripheral resistance in the spiral
arteries due to the shift in vasodilatory prostaglandins leading the vessels to
become fragile and damageable.

The
mechanisms that cause dysfunctional uterine bleeding in ovulatory woman seem to
be more complex as an array of functional abnormalities in the endometrium can
be possible. It seems that the disruption is prostaglandins can cause defects
in haemostasis however other molecules such as matrix metalloproteinases have also
been implicated in the disorder where MMP levels have been elevated in woman
with ovulatory DUB and may contribute to abnormally rapid breakdown of the
endometrium.

 

To
conclude, the exact abnormalities in the endometrium that lead to the two types
of dysfunctional uterine bleeding have not been pinpointed but it is evident
that there are several mechanisms that are definitely credible. Anovulatory DUB
is strongly associated with dysregulation of the HPG and its hormones,
predominantly the effects of unopposed oestrogen on the endometrium. Abnormalities
in endometrial function specifically the shift of prostaglandins towards a
vasodilatory phenotype is linked to ovulatory DUB. In saying this, it is
extremely important to understand possible mechanisms that cause dysfunctional
uterine bleeding in order to diagnose and treat it appropriately.