Ovarian and menstrual cycles

INTRODUCTION

 Males must have excellent spermatogenesis and ejaculatory function, while females
must have an exquisitely controlled hypothalamic-pituitary-ovarian (HPO) axis and
endometrial preparation.
 The HPO axis controls steroidogenesis and folliculogenesis (oogenesis) in the ovary,
which results in monthly ovulation.
 This is replicated in cyclic endometrial preparation in the uterus for pregnancy
implantation or cyclic menstruation in the absence of pregnancy implantation.
 Understanding the control of ovarian and menstrual function is thus critical to the
sensible treatment of many gynecological illnesses.
 These include delayed puberty, amenorrhea, anovulatory infertility, irregular uterine
hemorrhage, and ovarian stimulation in the context of assisted reproduction treatment.
 This chapter will cover the fundamentals of the HPO axis compartments that govern the
ovarian and menstrual cycles.

Summary
 Successful human reproduction depends on optimal spermatogenesis and
ejaculatory function in males, and an exquisitely regulated hypothalamic–
pituitary–ovarian (HPO) axis and endometrial preparation in females.
 This is mirrored in cyclic endometrial preparation in the uterus for
implantation of a pregnancy or cyclic menstruation in the absence of
implantation.
 Understanding the regulation of ovarian and menstrual function is
therefore crucial to the rational management of many gynaecological
disorders.
 These include delayed puberty, amenorrhoea, anovulatory infertility,
abnormal uterine bleeding and also ovarian stimulation in assisted
reproduction treatment.
 In this chapter we will address the basic facts about the
different compartments of the HPO axis controlling the ovarian
and menstrual cycles.
THE HPO AXIS

The hypothalamus
 The ventromedial nucleus of the hypothalamus includes neurons that secrete
gonadotrophin-releasing hormones (GnRH).
 These neurons would have moved from the olfactory placode during foetal
development.
 Failure of these neurons to migrate results in congenital lack of GnRH or
hypogonadotropic hypogonadism, which is commonly coupled with anosmia (Kalman’s
syndrome).
 The hypothalamic GnRH center receives afferent neurons from the limbic system,
olfactory center, occipital cortex, and other hypothalamic nuclei that govern energy
metabolism and stress response.

 These neurons produce GnRH pulsatile into the hypothalamic hypophyseal portal
circulation throughout pregnancy and immediately after delivery.
 The neurons in the anterior pituitary activate the GnRH receptor-bearing gonadotrophs,
resulting in the production and pulsatile release of gonadotrophins (FSH and LH).
 Because the quantity of GnRH reaching the systemic circulation is relatively low and its
half-life is very brief (2 minutes), GnRH pulses are difficult to monitor.
 Instead, LH pulses (half-life of 20 minutes) in the circulation can be quantified and so
utilized as an indirect measure of GnRH pulses.
 GnRH pulsatile secretion is required for gonadotrophin secretion and ovarian activity to
be maintained.
 Sustained exposure to GnRH (as seen in the use of GnRH analogues) causes an initial
increase in gonadotrophins (flare response), which is followed by down-regulation and
desensitization of GnRH receptors, resulting in very low levels of gonadotrophins and
ovarian steroid hormones after 10-14 days.
 The GnRH pulse generator is totally repressed shortly after birth and stays so until
adolescence.
 It is thought that reaching a certain amount of fat content causes leptin hormone
signaling from adipose tissue, which releases the GnRH pulse generator from
prepubertal inhibition, resulting in the onset of puberty.
 Various endocrine and paracrine regulators regulate the hypothalamus GnRH pulse
center during the reproductive years.
 Some of them, such as leptin, insulin, activin, and high amounts of estrogens during
ovulation, have a stimulatory impact.
 Others, such as ghrelin, inhibin, corticotrophin-releasing hormone (CRH), thyrotrophin-
releasing hormone (TRH), prolactin, estrogens, progestins, androgens, opioids, and
melatonin, have an inhibitory impact.
 Kisspeptin (stimulatory), pro-opiomelanocortin (stimulatory), neuropeptide Y
(inhibitory), dopamine (inhibitory), GABA, serotonin, and norepinephrine are the
primary neuropeptide and amine transmitters used by these regulators.
 As a result, reproductive function (as begun by GnRH pulses) is influenced by energy
(leptin, insulin, ghrelin), stress (CRH, TRH, opioids), gonadal signals (estrogens,
progestins, androgens, inhibin’s, activin), and light/dark signals (melatonin).
 Various pharmaceutical treatments that modify neurotransmitter levels can also have an
effect on reproductive function.
 The frequency and amplitude of GnRH pulses are determined by the balance of these
signals, as well as their timing, length, and amplitude.
 For example, the quick rise of estrogens after ovulation causes the LH surge, but a
persistent level of GnRH suppresses gonadotrophins.
 Other pituitary hormones, such as prolactin, have an inhibitory influence on GnRH and
gonadotrophin release.
 Pathological disorders that disrupt or damage the hypothalamic hypophyseal portal
circulation cause disturbances in GnRH pulses and hypogonadotropic hypogonadism (as
part of hypopituitarism).

CLINICAL POINTS
The down-regulated GnRH receptors, following prolonged
administration of a GnRH analogue, are responsible for the
pituitary suppression and prevention of natural ovulation in
cycles of in-vitro fertilisation (IVF). A similar effect has been
achieved, although for a shorter period, using GnRH
antagonists, which act by competitive blockade of GnRH
receptors rather than down-regulating the GnRH receptors.
In GnRH antagonist cycles, the GnRH agonist can be used to
initiate a surge of LH, similar to natural cycles, with less risk of
inducing ovarian hyperstimulation syndrome.
An exaggerated positive feedback of leptin in obese women
and patients with polycystic ovarian syndrome leads to an
increase in GnRH/LH pulse frequency, with an increase in
ovarian androgen production leading to chronic anovulation.
On the other hand, there is a subset of morbidly obese
women in whom there is a congenital leptin deficiency with
increased caloric intake and low FSH/LH levels.
Stress- and/or weight-related amenorrhoea are due to
combined inhibitory signals by the neuropeptide Y and stress
hormones, leading to suppressed GnRH secretion and
functional hypothalamic amenorrhoea.
summary
 The hypothalamus contains neurons secreting gonadotrophin- releasing
hormones (GnRH) in the ventromedial nucleus.
 These neurones would have migrated in fetal life from the olfactory placode.
 Here the neurons stimulate the GnRH receptor-bearing gonadotrophs in the
anterior pituitary resulting in the synthesis and pulsatile secretion of
gonadotrophins (FSH and LH).
 The amount of GnRH reaching the systemic circulation is very low and its half-life
is very short (2 minutes); therefore GnRH pulses cannot be easily measured.
 Sustained exposure to GnRH (as seen in the use of GnRH analogues) leads to an
initial increase of gonadotrophins (flare response) which is followed after 10–14
days by down-regulation and desensitisation of GnRH receptors with subsequent
very low levels of gonadotrophins and ovarian steroid hormones.
 It follows that reproductive function (as initiated by GnRH pulses) is under the
influence of energy levels (leptin, insulin, ghrelin), stress (CRH, TRH, opioids),
gonadal signals (oestrogens, progestins, androgens, inhibins, activin) and
light/dark signals (melatonin)

The pituitary gland

 FSH and LH, pituitary gonadotrophins, are both glycoprotein hormones.
 These hormones share an alpha unit with other glycoprotein hormones including
thyroid stimulating hormone (TSH) and human chorionic gonadotrophin (hCG), but each
has its own beta subunit.
 All of these hormones stimulate transmembrane G-protein receptors, resulting in a rise
in cyclic adenosine monophosphate (cAMP).
 These receptors are cross-responsive to the numerous glycoprotein hormones.
 From adolescence onwards, the pituitary gland secretes gonadotrophins primarily in
response to GnRH pulses.
 GnRH receptors are membrane receptors that are down-regulated by prolonged GnRH
exposure in gonadotrophs.
 Because the FSH hormone has a half-life of 4 hours and is influenced by both GnRH and
gonadal hormones, its pulses do not properly follow GnRH pulses.
 LH pulses with a short half-life mirror GnRH pulse more accurately.
 In the follicular phase of ovarian cycles, these LH pulses are greater in frequency (every
60-90 minutes) and lower in amplitude, compared to the lower frequency (120-160 min)
and higher amplitude signals in the luteal phase.

 CLINICAL POINTS
The similar structural activity of hCG and TSH explains the transient hyperthyroidism seen in states of incre
Spontaneous activating mutations of G-protein linked to receptors of glycoprotein pituitary hormones lead

Summary
 Pituitary gonadotrophins FSH and LH are both glycoprotein hormones
that act on transmembrane G-protein receptors that cause an increase in
cyclic adenosine monophosphate (cAMP). The gonadotrophins are
secreted from the pituitary gland mainly in response to GnRH pulses from
puberty onwards.
 The GnRH receptors are membrane receptors which are down-regulated
by sustained exposure of gonadotrophs to GnRH.
 The FSH hormone has a half-life of 4 hours and is under the influence of
both GnRH and gonadal hormones.
 LH pulses, with a short half-life, are a more accurate reflection of GnRH
pulses.
 These LH pulses are of higher frequency and lower amplitude in the
follicular phase of ovarian cycles, compared to the lower frequency and
higher amplitude signals in the luteal phase.

The ovary
 Embryologically, ovarian tissue is made up of three kinds of cells:
1) Primordial germ cells are produced from endodermal cells of the yolk sac and move to
the vaginal ridge during 6 weeks of intrauterine life. The primordial germ cells
proliferate and begin to differentiate into oogonia during the sixth to eighth week of
development.
2) Coelomic (sex cord) cells grow into granulosa cells, which surround the oogonia to
produce the primordial follicles.
3) Mesenchymal (sex stromal) cells, from which theca cells and other ovarian stromal cells
develop.
  The germ cells and accompanying sex cord and sex stromal cells are not differentiated
until 10 weeks of gestation, and the gonadal ridges are bipotential gonads.
 These gonads develop into ovaries because to a lack of paracrine factors encoded by
genes in the Y chromosome's sex determination region (SRY).

THE OVARIAN CYCLE

Gonadotrophin-independent phase
 Some germ cells (oogonia) begin to initiate meiosis at 12 weeks of gestation and
develop into primary oocytes surrounded by flattened granulosa cells to create
primordial follicles.
 Primary oocytes are halted during the prophase of the first meiotic division (diploid cell).
 The remaining oogonia undergo continuous mitosis and reach a peak population of 5-6
million at 20 weeks of gestation.
 Only those primordial oocytes that are surrounded by flat, spindly follicular or
pregranulosa cells survive.
 A basement lamina surrounds this oocyte-pregranulosa cell complex.
 A primordial follicle is the original oocyte with its surrounding single layer of
pregranulosa cells during this stage of development.
 Primordial follicles range in size from 30 to 60 m.
 The first primordial follicle occurs around 6 weeks into intrauterine life, and the
creation of primordial follicles is completed approximately 6 months following delivery.
 The initial stage of follicular development occurs when a primordial follicle transforms
into a primary follicle.
 The spindle cells of the primordial follicle transform into cuboidal cells, resulting in the
formation of the main follicle.
 Furthermore, the oocyte grows in size.
 As a result, the major follicle houses a bigger primary oocyte surrounded by a single
layer of cuboidal granulosa cells.
 A main oocyte is surrounded by many layers of cuboidal granulosa cells in the secondary
follicle.
 A primary follicle's granulosa cells grow and give rise to multiple layers of cells.
 Furthermore, stromal cells develop, surround the follicle, and eventually become theca
cells.
 These theca cells may be seen on the follicle's basement membrane.
 The oocyte expands to a diameter of roughly 120 m.
 As the developing follicle grows in size, the number of granulosa cells increases to
around 600, and theca cells differentiate.
 The creation of capillaries and an increase in the circulatory supply to growing follicular
units accompany the transition to secondary follicles.
 The granulosa cells leak fluid into the follicle's core, forming a fluid-filled region known
as the antrum.
 At this point, the follicle is referred to as a tertiary follicle.
 Gap junctions occur between theca and granulosa cells in tertiary follicles.
 Tight junctions and desmosomes also exist between neighbouring cells.
 Gap junctions may also occur between the oocyte and the granulosa cells closest to the
oocyte and serve as pathways for nutrients and paracrine signals to be transported from
the granulosa cells to the oocyte and vice versa.
 A layer of mucopolysaccharides (the zona pellucida) is secreted by the granulosa cells
nearest to the egg.
 These phases occur in the absence of gonadotrophin stimulation and in response to
local autocrine and paracrine hormones such as growth differentiation factor (GDF) and
anti-Mullienian hormone (AMH).
 The latter is made by granulosa cells and enters the systemic circulation in proportion
to the secondary follicle pool.
 Secondary follicles undergo apoptosis and atresia in the absence of additional
gonadotrophin stimulation.
 This process of gonadotrophin-independent recruitment to secondary follicles and
death in the absence of gonadotrophins continues throughout intrauterine, prepubertal,
and reproductive life until follicular pool depletion at menopause.
 Because, unlike spermatogenesis, atretic follicles cannot be regenerated, the ovarian
reserve of follicles is a limited pool.
 The number of primordial follicles is around 1-2 million at birth, declines to
approximately 400,000 at the onset of adolescence, and is fewer than 1000 by the age
of menopause, with only approximately 500 oocytes destined to ovulation during a
woman's reproductive career.
 Individual females' rates of loss of the primordial follicle pool vary, as does the age of
loss of fertility and menopause (40-55 years).
 Natural fertility is thought to be lost roughly ten years before menopause (fixed-interval
theory).
 The gonadotrophin-independent phase lasts around 74-80 days.

Summary
 By 12 weeks of gestation some germ cells (oogonia) start to enter into meiosis
and become primary oocytes surrounded by flattened granulosa cells to form
primordial follicles.
 Primordial follicles are 30–60 μm in diameter.
 Thus, the primary follicle contains a larger primary oocyte that is surrounded by a
single layer of cuboidal granulosa cells.
 In tertiary follicles, gap junctions are formed between theca and granulosa cells.
This process of gonadotrophin-independent recruitment to secondary follicles
and apoptosis in absence of gonadotrophins is continuous during intrauterine,
pre-pubertal and reproductive life till depletion of the follicular pool at the age of
menopause.
 The rate of loss of the primordial follicle pool is variable among individual
females, with variable age of loss of fertility and menopause (40–55 years).

Gonadotrophin-dependent phase
 In the absence of pituitary gonadotrophins, the ovary's developing follicles will undergo
atresia (apoptosis).
 The surge in pituitary gonadotrophins throughout the reproductive years, caused by the
release of the hypothalamus GnRH pulse center from pre-pubertal inhibitory signals,
results in the rescue of preantral/antral follicles.

 The quantity of rescued and recruited follicles is determined by the pool of secondary
follicles accessible at the time of FSH increase, which is connected to the total pool of
primordial follicles in the ovary (ovarian reserve).
 It is also affected by the level of FSH and the duration of the increase (selection
window).
 The stimulation of aromatase enzyme activity in the granulosa cells, which transforms
androgens synthesized in theca cells into estrogen under the influence of LH, is a vital
stage in this rescue process.
 As a result, the two gonadotrophins, FSH and LH, act preferentially on the ovary's two
primary steroid-producing cells (granulosa and theca cells).
 FSH's major impact is to rescue granulosa cells (and oocytes) from atresia and to
stimulate aromatase activity.
 LH's primary function is to stimulate steroidogenesis by acting on theca cells to
synthesize androgenic substrates, which are then transformed into estrogens in the
granulosa cells.
 This is referred to as the two cell, two gonadotrophins hypothesis.
 The result of this coordinated activity of FSH and LH is the shift of the secondary pre-
antral follicle microenvironment from one dominated by androgens to one dominated
by estrogens.
 The latter causes further granulosa and theca cell proliferation, as well as accelerated
production of estrogen and peptide hormones (inhibin’s, activin, follistatin) and the
formation of a cavity (antrum) in which the oocyte is surrounded by a few layers of
granulosa cells projecting into the cavity.
  The fluid in the follicular cavity includes a plethora of growth factors and signaling
molecules that are engaged in bidirectional communication between the oocyte and the
surrounding granulosa.

Summary
 In the mid-follicular phase (usually on day 7–8 of a 28-day cycle) selection of a
dominant follicle (which is usually over 10 mm in diameter at that stage) occurs
by the effect of rising oestrogen and inhibin A levels produced by actively growing
follicles.
 This results in a negative feedback effect on the pituitary gonadotrophin (FSH/LH)
secretion, and starvation of most of the follicles of the necessary FSH to support
granulosa cell proliferation and aromatase activity.
The dominant follicle expands in size with an exponential rise of oestradiol levels.
 In natural cycles selection of a single dominant follicle and monofollicular
ovulation is the rule, whilst in ovarian stimulation cycles the prolonged
exogenous FSH stimulation leads to support and survival of more than one
follicle.
 The dominant follicle accumulates more fluid in the follicular cavity and its
granulosa cells become organised into three compartments: mural granulosa
cells surrounding the antrum; cumulus oophorus (which is a stalk of granulosa
cells connecting the oocyte to the mural granulosa); and corona radiata (which is
a layer of granulosa cells in direct contact with the oocyte).
The latter separates it from the mural granulosa and outer theca cells.

Inhibins/activin/follistatin and
insulin-like growth factors
 Growing follicle granulosa cells release a set of proteins that are critical for controlling
the HPO axis.
 FSH stimulates granulosa cells to release activin and inhibin A during the early follicular
phase.
 Activin promotes granulosa cell growth and aromatase enzyme synthesis while boosting
FSH receptors.
 Activin also suppresses the synthesis of androgens by theca cells.
 Inhibin A inhibits pituitary FSH synthesis and release while also stimulating theca cell LH
receptors and androgen production.
 The granulosa cells also release follistatin, which interacts with activin and inhibits its
function; it also directly reduces pituitary FSH production and secretion.
 Inhibin A activity overtakes activin as the follicular phase advances.
  This makes it easier to identify the dominant follicle capable of maintaining
steroidogenesis in the face of diminishing FSH levels.
 Concurrently, insulin-like growth factor-2 (IGF-2) and its binding protein (IGF2 BP)
influence intra-ovarian activity of FSH and LH, resulting in a higher concentration of IGF2
BP and a lower concentration of bioavailable IGF-2 in androgen-dominant follicles.
 This results in diminished FSH effect on the granulosa and decreased steroidogenic
activity, resulting in decreased estradiol production and follicular atresia.
 In the context of hyperinsulinemia and hyperandrogenemia, this might be one of the
processes causing follicular arrest and anovulation in polycystic ovarian syndrome.
 Inhibin B is released by granulosa cells recruited from the secondary follicle pool to
enter the gonadotrophin-dependent phase during the lute follicular transition and early
follicular phase.

Summary
 The granulosa cells of the growing follicles secrete a group of proteins which are
important for regulating the HPO axis.
 In the early follicular phase FSH induces granulosa cells to secrete activin and
inhibin A. Activin augments FSH action by increasing its receptors and up-
regulates granulosa cell proliferation and aromatase enzyme production.
 Activin also inhibits the theca cells, androgen production.
 inhibin A activity predominates over activin.
 This facilitates the selection of the dominant follicle which is able to maintain
steroidogenesis in the face of declining FSH levels.
 In the luteo-follicular transition and early follicular phase, inhibin B is secreted by
the granulosa cells, recruited from the secondary follicles pool, to enter the
gonadotrophin-dependent phase

The dominant follicle

 The action of increased estrogen and inhibin A levels produced by actively
developing follicles causes selection of a dominant follicle (which is normally
above 10 mm in diameter at that point) in the mid-follicular phase (usually on
day 7-8 of a 28-day cycle).
 This has a negative feedback impact on pituitary gonadotrophin (FSH/LH)
production, depriving most follicles of the FSH required to maintain granulosa
cell growth and aromatase activity.
 The dominating follicle grows in size as estradiol levels climb exponentially.
 This exacerbates the fall in FSH levels and leads to atresia of the remaining follicles.
 In natural cycles, a single dominant follicle and monofollicular ovulation are the norm,
however in ovarian stimulation cycles, sustained exogenous FSH stimulation leads to the
maintenance and survival of several follicles.
 The dominant follicle accumulates more fluid in the follicular cavity, and its granulosa
cells divide into three compartments:
o mural granulosa cells surrounding the antrum,
o cumulus oophorous (a stalk of granulosa cells connecting the oocyte to the
mural granulosa),
o and corona radiata (a layer of granulosa cells directly in contact with the
oocyte).
 The oocyte, together with its corona radiata and cumulus oophorous, is immersed in
follicular cavity fluid.
 It is separated from the mural granulosa and outer theca cells by the latter.
 The follicle is now known as the Graafian follicle or pre-ovulatory follicle.
 Independent of FSH stimulation, the Graafian follicle continues to generate estrogen
and has the maximum number of granulosa cells and estradiol levels with the lowest
androgen-to-estrogen ratio.
 This follicle also produces LH receptors in the granulosa cells, which aids in oocyte
maturation and prepares the follicle for the ovulatory stimulation of the LH surge.
 After ovulation, the LH receptors enable enough progesterone synthesis by the
luteinized granulosa cells of the corpus luteum.

Summary
 In the mid-follicular phase (usually on day 7–8 of a 28-day cycle) selection of a
dominant follicle (which is usually over 10 mm in diameter at that stage) occurs
by the effect of rising oestrogen and inhibin A levels produced by actively growing
follicles.
 This results in a negative feedback effect on the pituitary gonadotrophin (FSH/LH)
secretion, and starvation of most of the follicles of the necessary FSH to support
granulosa cell proliferation and aromatase activity.
 The dominant follicle expands in size with an exponential rise of oestradiol levels.
 In natural cycles selection of a single dominant follicle and monofollicular
ovulation is the rule, whilst in ovarian stimulation cycles the prolonged
exogenous FSH stimulation leads to support and survival of more than one
follicle.
 The dominant follicle accumulates more fluid in the follicular cavity and its
granulosa cells become organised into three compartments: mural granulosa
cells surrounding the antrum; cumulus oophorus (which is a stalk of granulosa
 cells connecting the oocyte to the mural granulosa); and corona radiata (which is
a layer of granulosa cells in direct contact with the oocyte).
 The latter separates it from the mural granulosa and outer theca cells.

Ovulation
 When estradiol (E2) levels reach 300-400 pg/ml (500-900 pmol/L) (which generally
corresponds to a follicle size of 18-20 mm), the pituitary gland responds by increasing LH
levels to around 15-30 IU/L.
 This causes a chain reaction of alterations in the Graafian follicle, resulting in ovulation
within 36 hours (34-39 hours) following the commencement of the LH surge.
 The LH surge causes the Graafian follicle and ovary to undergo the following changes:

1. The oocyte resumes meiosis with the extrusion of the first polar
body (the oocyte becomes haploid), and the oocyte is halted in
the metaphase of the second meiotic division, which is
completed with the extrusion of the second polar body during
fertilization.
2. Induction of angiogenesis and enhanced vascularity and
capillary permeability in theca cell layers, resulting in increased
follicular fluid production and intrafollicular pressure.
3. Synthesis and release of different prostaglandins, which aid in
increasing blood flow in the follicular wall and stimulating
smooth muscle cells inside the ovarian stroma, which aid in
oocyte expulsion.
4. Activation of matrix metalloproteinases and other proteolytic
enzymes at the follicular site that degrade the follicular wall and
ovarian capsule to allow follicular rupture and egg release, i.e.,
ovulation.
5. Shortly before ovulation, LH promotes progesterone production
in the granulosa and theca cells. This amplifies the LH surge and
guarantees appropriate luteinization of theca and granulosa
cells, as well as corpus luteum function afterwards.
 As a result of these modifications, the follicular wall ruptures, releasing follicular fluid as
well as the oocyte and its surrounding cumulus cells.
 This is generally taken up by the tube's fimbrial end and delivered to the ampullary
region of the fallopian tube, where fertilization might occur.
 The gonadotrophin-dependent phase (follicular phase of the ovarian cycle) lasts around
14 days in a standard 28-day cycle.
 However, this varies between individuals, resulting in varied follicular phase lengths and
consequent varying menstrual cycle lengths because the corpus luteum lifetime is
almost stable at around 14 days.
  Ovulation timing is so difficult to anticipate in advance; nevertheless, a fertile time
during which ovulation is likely to occur may be predicted using the woman's menstrual
history and cycle lengths.

Summary
 When the estradiol (E2) levels peak to 300–400 pg/ml (500–900 pmol/L)
(which usually coincides with a follicle size of 18–20 mm), the pituitary
gland responds by a surge of LH levels to about 15–30 IU/L. This leads to a
cascade of changes in the Graafian follicle and leads to ovulation within
36 hours (34–39 hours) of the onset of the LH surge.
 Induction of angiogenesis and increased vascularity and capillary
permeability in the theca cell layers with increased production of follicular
fluid and increase in intrafollicular pressure.
 Synthesis and secretion of various prostaglandins that help increase blood
flow in the follicular wall and stimulate smooth muscle cells within the
ovarian stroma that help expel the oocyte.
 This is usually picked up by the fimbrial end of the tube, and is
transported to the ampullary part of the fallopian tube where fertilization
may occur.
 In a regular 28-day cycle the gonadotrophin-dependent phase (follicular
phase of the ovarian cycle) lasts about 14 days.
 The timing of ovulation is therefore difficult to predict prospectively;
however, a fertile period when ovulation is likely to occur can be predicted
using the woman’s menstrual history and cycle lengths.

The luteal phase

 After the oocyte-cumulus complex is released, the follicular antrum fills with blood and
new blood vessels develop.
 The theca-lutein cells become luteinized, and the resultant structure is known as a
corpus luteum.
 In response to LH pulses, the corpus luteum generates estrogen, progesterone (P4), and
inhibin A.
 These, in turn, reduce pituitary FSH and LH output.
 In the face of diminishing FSH and LH levels, the corpus luteum only operates for
approximately 10 days, with peak activity around 7 days after ovulation (mid-luteal
progesterone peak on day 21 of a 28-day cycle).
  If no pregnancy occurs, it undergoes an apoptosis and regression phase lasting around 4
days.
 The corpus luteum has a reasonably regular life span of 14 days in the absence of
pregnancy.
 Falling estradiol and progesterone levels cause apoptosis and endometrial loss.
 Falling ovarian steroid levels relieve the hypothalamus and pituitary of the negative
feedback effect, resulting in a rise in FSH levels and a new cycle of secondary follicle
recruitment.
 The luteo-follicular transition phase is distinguished by rising FSH levels, low estradiol
and progesterone levels, and elevated inhibin B levels released by recruited follicle
granulosa cells.
 If a pregnancy develops, the hCG generated by the trophoblast of the implanting
embryo saves the corpus luteum from apoptosis and atresia, allowing the corpus luteum
to function and produce progesterone until 10-12 weeks' gestation, when the placenta
takes over.

Summary
 After the release of the oocyte–cumulus complex, the follicular antrum is
filled with blood and new blood vessels forms.
 These in turn suppress FSH and LH secretion by the pituitary.
 It then enters into an apoptosis and regression phase of about 4 days if
pregnancy does not occur.
 The falling estradiol and progesterone levels lead to apoptosis and
shedding of the endometrium.
 If pregnancy occurs the hCG produced by the trophoblast of the
implanting embryo rescues the corpus luteum from apoptosis and atresia,
enabling the corpus luteum to function and produce progesterone till 10–
12 weeks’ gestation when the placenta takes over this function

THE MENSTRUAL CYCLE

 The endometrium experiences cyclic changes that mimic the action of hormones
released by the ovary's developing follicles and corpus luteum.
 The endometrium is regenerated from the basalis layer in the early follicular phase after
its superficial layer was removed during the previous cycle's menstruation. The estradiol
released by the ovary causes vigorous mitosis and proliferation of the endometrial
glands and stroma.
 This causes the endometrium's thickness to expand from 2-3 mm to 6-8 mm at the
conclusion of this proliferative period.
 The endometrium is regenerated from the basalis layer in the early follicular phase after
its superficial layer was removed during the previous cycle's menstruation.
 The estradiol released by the ovary causes vigorous mitosis and proliferation of the
endometrial glands and stroma. This causes the endometrium's thickness to expand
from 2-3 mm to 6-8 mm at the conclusion of this proliferative period.
 The stroma appears edematous, with an increase in the number and coiling of spiral
arteries, as well as pericapillary leukocytic and cellular infiltrates, a condition known as
decidualization.
 The result of epithelial alterations is the production of adhesion molecules such as
integrins and glycodelin’s, which facilitate the attachment of the blastocyst that
commences the implantation process (in the case of successful fertilization).
 The recruitment of immune cells (natural killer cells, dendritic cells) that help regulate
trophoblastic invasion and induce alterations in the spiral arteries that lead to the
formation of the early placenta is a result of stromal decidualization.
 The peak of secretory changes in the endometrium occurs 7-9 days following ovulation,
when the endometrium is most susceptible to blastocyst implantation, known as the
implantation window.
 40 Ovulation

30
LH
FSH

mL
20

10

0
–14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14
1000 D ays 60

50
800

40
600

P4 nm ol/L
E2 pm ol

P4
30
E2
400
20

200 10

0 0
80
–14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14
D ays

60
Inhibin B
Inhibin p m ol

Inhibin A

40

20

0
–14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 12 14
D ays

Fig. 71.1 Depiction of the changes of pituitary hormones (FSH/LH), ovarian steroids (E2, P4) and ovarian peptide hormones in a normal ovarian and
menstrual cycle

 If fertilization happens and a blastocyst successfully implants in the endometrium, the

implanting embryo's trophoblast secretes hCG, which saves the corpus luteum.
 This increases the longevity of the corpus luteum and keeps progesterone secretion
going until around 10 weeks of pregnancy, when the growing placenta takes over
hormone synthesis (luteo-placental shift).
 Pregnant women will have physiological amenorrhea as a result of maintaining estrogen
and progesterone production and decidua stability.
 If there was no fertilization or a blastocyst failed to implant, the reducing corpus luteum
function (beginning around day 10-12 following ovulation and practically complete by
day 14) is related with lowering estrogen and progesterone levels.
 This, in turn, causes apoptosis in the endometrium, resulting in the release of
prostaglandins and lysosomal enzymes from the cells, causing waves of vasoconstriction
and ischemia.
 Further disintegration of blood vessels and cells occurs, followed by vasodilation,
allowing blood cells (erythrocytes, leukocytes, platelets) and proteolytic enzymes
(metalloproteinases, enkephalinases, fibrinolysins) to enter the endometrial stroma.
 These waves of vasoconstriction and vasodilation, together with apoptosis and
proteolysis, result in endometrial sloughing at the confluence of the superficial and
basal layers, resulting in monthly bleeding.
 In conjunction with these changes, the endometrium's produced prostaglandins, as well
as myometrial cells under the influence of lowering progesterone levels, cause
myometrial contractions.
 This causes the menstrual blood to be expelled from the uterus.3,4
 A regular menstrual cycle lasts 2-6 days, and the amount of blood is usually 20-80 ml.
 The increased estradiol level induced by the recruited follicles causes the endometrium
to heal and reconstruct quickly, resulting in the end of the menstrual period.
 Menstrual bleeding in ovulatory cycles (estrogen/progesterone withdrawal bleeding) is
synchronized and less prolonged, and is associated with menstrual cramps due to higher
levels of prostaglandins, whereas menstrual bleeding in anovulatory dysfunctional cycles
is typically prolonged, erratic, heavy, and painless.
 In cases of dysfunctional menorrhagia (prolonged and/or heavy menstruation caused
primarily by anovulation and/or dysfunctional molecular changes in the endometrium in
the absence of significant pathological changes), progestins alone or sequential
estrogens/progestin treatment may be beneficial to mimic the estrogen/progesterone
withdrawal bleeding in normal cycles.
 Prostaglandin synthetase inhibitors (for example, the nonsteroidal anti-inflammatory
drug mefenamic acid) are also used to treat dysfunctional menorrhagia.
CLINICAL POINTS
Luteal phase defect is a condition characterised by either a short luteal phase or a subnormal secretion of prog
In a healthy pregnancy the hCG level usually shows a long linear rise every 48 hours until it reaches a peak of ar

gestations in hCG levels, and the interpretations of findings should be in conjunction with transvaginal ultrasound scans and

KEY POINTS
The ovarian and menstrual cycles are tightly coordinated in order to ensure a receptive endometrium at the tim
The pituitary hormones LH and FSH are regulated by feedback from the ovarian sex steroids (estrogens and pro
Advancements in IVF are underpinned by an understanding of the interplay between the pituitary gonadotroph
the development of drugs to influence the menstrual cycle, including injectable gonadotrophins to stimulate m
Anovulation should be investigated by using timed measurements of FSH, LH and progesterone, sometimes wit
Underlying cause for anovulation needs to be established before considering treatment options.
Summary
 The endometrium undergoes cyclic changes which mirror the effect of
the hormones produced by the growing follicles and corpus luteum in
the ovary.
 This leads to an increase in the thickness of the endometrium from 2–
3 mm to about 6–8 mm by the end of this proliferative phase.
 The effect of stromal decidualization is recruitment of immunological
cells (natural killer cells, dendritic cells) that help regulate the
trophoblastic invasion and effect changes in the spiral arteries that
lead to the development of the early placenta.
 This prolongs the lifespan of the corpus luteum and maintains
progesterone secretion till about 10 weeks’ gestation when the
developing placenta takes over the hormonal production (luteo-
placental shift).
 The rising estradiol level caused by the recruited follicles leads to
rapid repair and rebuilding of the endometrium and the end of the
menstrual phase.
 Menstrual bleeding in ovulatory cycles (estrogen/progesterone
withdrawal bleeding) is characterized by being synchronized and less
prolonged and associated with menstrual cramps due to higher levels
of prostaglandins, while in anovulatory dysfunctional menses are
usually prolonged, erratic, heavy and painless.