(Gyne) 1.2 Reproductive Endocrinology - CMM

GYNECOLOGY
1.2: REPRODUCTIVE ENDOCRINOLOGY (ppt only)

FEU-‐NRMF Institute of Medicine

Medcine2017
REPRODUCTIVE ENDOCRINOLOGY
• The hypothalamic control of gonadotropin is only
stimulatory whereas the hypothalamic control of
prolactin is both inhibitory-‐PIF and stimulatory-‐PRF.

GnRH Route of Secretion:
Hypothalamus, Anterior hypothalamus, Medial basal/
tuberal hypothalamus (arcuate nucleus)à
Tuberoinfundibular Tract à Median Eminence (part of
the neurohypophysis)à Portal CirculatioàAnterior
lobe of the pituitary

Major route: Cyclic release
The HPO INTERACTIONS
• Menstruation and ovulation are brought about by
integrated events, which happen within the different
components of the reproductive system.
• The cyclicity of these events lies on the integrity of
three processes:
ü Activity of GnRH pulses
ü Pituitary secretion of gonadotropins
ü Estradiol positive feedback for preovulatory LH
surge, oocyte maturation and corpus luteum
formation
Upon activity of the GnRH pulse generator, bolus of GnRH
is released into the pituitary portal circulation. The
pituitary gonadotrophes respond by discharging luteinizing
hormone (LH) & Follicle-‐stimulating hormone (FSH) into
the circulation. The hormones subsequently stimulate
follicular development, ovulation and sex steroid 1. The two areas where GnRH is produced are the cell
production. Levels of estradiol regulate further release of bodies of neurons in the anterior hypothalamus
gonadotropins and GnRH. and the arcuate nucleus in the medial basal
(tuberal) hypothalamus.
Gonadotropin Releasing Hormone (GnRH) Structure 2. GnRH is transported from here through the axons
of these neurons (tuberoinfundibular tract) to
reach the median eminence (infundibulum) upon
which GnRH is released directly into the portal
• GnRH is a decapeptide synthesized and released by circulation.
the arcuate nucleus in the hypothalamus 3. The portal circulation brings the hormone to the
• It is secreted as a 92-‐amino-‐acid precursor protein anterior lobe of the pituitary.
encoded in the short arm of chromosome 8 4. The circulation returns to the neurohypophyseal
• Primary receptors: located in the pituitary but have capillary plexus after leaving the anterior pituitary
also been found in other organs such that pituitary hormones can help regulate
• Primary function: stimulate pituitary synthesis and secretion of GnRH.
release of gonadotropins FSH and LH.
• GnRH receptor synthesis is also stimulated by the Minor Cyclic (Alternative Route: Tonic release)
hormone. Axons of the tuberoinfundibular tract can transport
Hypothalamic Gonadotropins Stimulatory, GnRH GnRH directly into the third ventricle where tanycytes
control Prolactin Stimulatory, PRF bring the hormone into the median eminence. (Low
Inhibitory, PIF grade continuous release)
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GYNECOLOGY 1.2: REPRODUCTIVE ENDOCRINOLOGY (ppt only) Medcine2017
Facilitator: Dr. A.D. Cruz
and amplitude of pulses. During the luteal phase, however,
there is a progressive lengthening of the interval between
pulses as well as a decrease in the amplitude. This variation
in pulse amplitude and frequency is directly responsible for
the magnitude and relative proportions of gonadotropin
secretion from the pituitary, although additional hormonal
influences on the pituitary will modulate the GnRH effect.

GnRH REGULATION OF SECRETION
• The contol of episodic GnRH secretion is extremely
important for the maintenance of normal
ovulatory cyclicity

GnRH SECRETION
Unique among Regulates secretion of FSH
releasing hormones and LH
Secreted in pulsatile
manner to be effective
(half-‐life 2-‐4mins)
• GnRH is unique because it simultaneously regulates
secretion of two hormones-‐FSH and LH and it does
this by itself being secreted in a pulsatile manner.
This continual pulsatile secretion of GnRH is
necessary because the hormone has a very short REGULATION: FEEDBACK LOOPS
half-‐life and undergoes proteolysis in 2-‐4 minutes The amplitude and frequency of pulses by the
after its release. The pulses vary in frequency and hypothalamus is regulated by:
amplitude throughout the menstrual cycle. Pulse • circulating levels of ovarian sex steroids estrogen
regulation is tightly controlled and progesterone (Long feedback
• In the first half of the cycle (Follicular Phase), the • loop)
pulses are frequent but of low amplitude and • gonadotropins through humoral input pathways
increases in both frequency and amplitude towards (Short feedback loop)
the late follicular phase. During the second half of • hypothalamic secretions such as neurotransmitters
the cycle (Luteal Phase) there is a decrease in both and neuromodulators through the neural input
frequency and amplitude of GnRH pulses. These pathway (Ultrashort feedback loop)
variations of the pulses are responsible for the
magnitude and relative proportions of gonadotropin NEUROTRANSMITTERS AND THEIR ROLE IN
secretions from the pituitary. REGULATION OF GnRH SECRETION
ü F-‐ 1 PULSE PER HOUR The Three Most Important are:
ü L-‐1 PULSE IN 2-‐3 HOURS • Dopamine-‐ a cathecholamine
Varies in Frequency and Amplitude duing cycle • Norepinephrine-‐ a catecholamine
Follicular phase Frequent, small amplitude • Serotonin-‐ an indolamine
Late follicular phase Greater frequency, higher Long feedback Stimulation and inhibitory
amplitude loop ovarian steroids (E2, P4)
Luteal phase Decreased frequency, high Stimulation and inhibitory by
amplitude nonsteroidal secretions (Inhibin,
Activin, Follistatin)
The follicular phase is Short Inhibition by gonadotropins (LH,
characterized by frequent feedback loop FSH)
small pulses of GnRH
Ultra-‐short Inhibition by GnRH
secretion. In the late
feedback loop Neurotransmitters and
follicular phase, there is an
increase in both frequency Neuromodulators and Brain
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peptides (Catheolamines, • Methyldopa blocks tyrosine hydroxylase and

dopamine, endogenous opiod blocks dopamine and NE production.
peptides) • Reserpine and Chlorpromazine interferes with
D, NE, and S storage and binding.
1. Cathecolamines: Modulate GnRH pulsatile release • TCAs inhibit reuptake of NTS.
by influencing the frequency and amplitude of • Propranolol, Phentolamine, Haloperidol,
pulses Cyproheptadine blocks hypothalamic receptors
Dopamine Inhibits GnRH release (indirectly
inhibits gonadotropins)
Inhibits Pituitary prolactin
secretion (Prl Inhibiting
hormone)
Norepinphrine Stimulatory to GnRH

2. Indolamine
Serotonin Does NOT affect GnRH release
Stimulates PRF, thus stimulating Prl
ultimately inhibiting GnRH

The secretion of GnRH secretion by the hypothalamus is

regulated or modified by the stimulatory and inhibitory
feedback effects of the ovarian steroids, estradiol and
progesterone, acting through the "long feedback loop", the
inhibitory feedback effect of the gonadotropins through the
"short feedback loop", inhibition of GnRH synthesis by
GnRH itself through an "ultrashort feedback mechanism",
and several neurotransmitters and neuromodulators within
the brain through a neural input pathway.

Biosynthesis of catecholamines
• The catecholamines are biogenic amines that have
a catechol group. Their biosynthesis in the adrenal
cortex and CNS starts from tyrosine.
1. Hydroxylation of the aromatic ring initially
produces dopa (3,4-‐dihydroxyphenylalanine). This
reaction uses the unusual coenzyme
tetrahydrobiopterin (THB). Dopa (cf. p. 6) is also
used in the treatment of Parkinson’s disease.
2. Decarboxylation of dopa yields dopamine, an
important transmitter in the CNS. In dopaminergic
neurons, catecholamine synthesis stops at this
point.
3. The adrenal gland and adrenergic neurons
• Pharmacologic agents may cause disorders such continue the synthesis by hydroxylating dopamine
as galactorrhea and oligoamenorrhea by into norepinephrine (noradrenaline). Ascorbic
altering neurotransmitter action on prolactin acid (vitamin C; see p. 368) acts as a hydrogen-‐
and GnRH release. transferring coenzyme here.
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4. Finally, N-‐methylation of norepinephrine yields GnRH Comparison
epinephrine (adrenaline). The coenzyme for this
reaction is S-‐adenosylmethionine.

The physiological effects of the catecholamines are
mediated by a large number of different receptors that
are of particular interest in pharmacology.
Norepinephrine acts in the autonomic nervous system
and certain areas of the brain. Epinephrine is also used
as a transmitter by some neurons.

NEUROMODULATORS AND BRAIN PEPTIDES
NEUROMODULATORS Opiods: ↓LH, ↓GnRH,
-‐ substances that ↑Prl Prostaglandin: GnRH Analogs Clinical Use:
affect the action of ↑GnRH Cathecolestrogens:
neurotransmitters Inhibit tyrosine OHlase
BRAIN PEPTIDES Neuropeptide Y
-‐ function as Angiotensin II
neurotransmitters but Somatostatin
have local autocrine Activin and Inhibin
and paracrine Follistatin
functions Galanin

GnRH Analogues

GnRH MOA: GnRHa administered à GnRH receptors
occupied and internalizedà initial LH and FSH surgeà
Loss of available GnRH receptorsà decreased LH and
FSH synthesis and release à suppression of follicular
development à decreased estradiol synthesis and
release
• GnRH AGONISTS have greater potency and longer half-‐
life than GnRH. Agonists initially cause a release of
• Administration of GnRH bolus results to a rapid
gonadotropins (FLARE effect) which lasts for 1-‐3 weeks.
increase in circulating LH (peaks at 30 mins) and in Then receptor saturation is achieved with continued use
FSH (peaks at 60 mins). Baseline levels return after and no further release of gonadotropins occur.
3 hours. Constant infusion produces a biphasic (DESENSITIZATION OR DOWN REGULATION). They are
release of LH but not FSH-‐the first pool being therefore useful and effective in conditions caused or
stored and the second pool being newly made LH aggravated by sex steroids.
molecules. But with continued infusion, • Adverse effects of these agents include bone
gonadotropin secretion stops as consequence of demineralization and hot flushes akin to
receptor saturation. menopause as the end result is lowered estradiol
• Maximal hormonal stimulation happens with only level. ADD BACK therapy which is the concomitant
a small percentage of receptors are occupied. At intake of low dose estrogen and/or progestins
this time, the unoccupied receptors become obviate these affects.
unresponsive to GnRH stimulation. This
refractoriness lasts for 12 to 72 hours. This is the GnRH Antagonist MOA: Pituitary-‐ovarian axis
basis for clinical applications of GnRH analogues. suppression without flare effectà complete with GnRH
for its receptorà prevent synthesis and release of
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LH/FSHà Induce immediate and transient FUNCTIONS: LH

hypogonadismà suppress gonadal steroidogenesis
• GnRH ANTAGONISTS were initially withdrawn due to
unacceptable effects of histamine release. Newer agents
(Nal-‐Glu) however have less of this problem. Antagonists
can lower serum LH after only one dose and NO flare
effect is seen. Ovulation is acutely inhibited and LH is
affected more than FSH while estradiol levels are lowered
at midcycle. These agents are primarily used for ART to
down regulate the HPO during ovarian stimulation cycles.

GONADOTROPINS: FSH and LH

-‐ Structural similarity Identical a-‐subunits different
b-‐subunits FUNCTION: FSH
-‐ Secretion common cell type: Basophillic cells

Structure: FSH and LH

The ovarian follicle showing arrangement of follicle
cells around the oocyte
• These are high molecular weight glycoprotein which
share similar α subunit as TSH and HCG and differ in
β subunits. LH has a half-‐life of 30 minutes and FSH
of 3.9 hours. They are synergistic in action. LH
primarily acts on the theca cells to induce
steroidogenesis. FSH acts on the granulosa cells to
stimulate follicular growth.
• Prepubertal: FSH release is greater than LH release
• Puberty and Reproductive age: LH release is greater

than FSH release
Hormone Production in the Graafian follicle
• Menopause: FSH is again greater than LH release
Theca cells Androstenedione

Testosterone
Physiologic secretion
Granulosa cells Estrone
• FSH release is greater than LH during puberty and
menopause Estradiol
• This preferential inhibition of FSH release during Corpus luteum Progesterone
the reproductive years results from increasing
levels of both estradiol and inhibin
• Physiologic secretion of gonadotropins from the OVARIAN STEROIDOGENESIS: Two-‐cell two-‐
pituitary requires intermittent GnRH stimulation gonadotropin hypothesis
which is accomplished under physiologic -‐ Compartmentalization of steroid hormone synthesis
circumstances by the pulsatile secretion of GnRH in the developing follicle
from the hypothalamus.
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receptor synthesis and expression, and granulosa cell
proliferation and differentiation.

Receptors for LH exist on the theca cells at all stages of the
cycle; they are on granulosa cells after the follicle matures
under the influence of FSH and estradiol, as well as on the
corpus luteum. Each gonadal target tissue cell contains
between 2000 and 30,000 membrane receptors. Maximal
stimulation of hormonal activity occurs when less than 5% of
these receptors are bound with hormone. The main action of
LH is to stimulate androgen synthesis by the theca cells and
progesterone syn-‐thesis by the corpus luteum through
stimulation of intracellular cAMP production ( Fig. 4-‐13 ). The
precise action of LH on granulosa cells has not been
determined, but it probably acts synergistically with FSH to
• LH acts on theca cells to produce androgens help follicular maturation. LH stimulates several other
(androstenedione and testosterone) which are then metabolic events in the ovary, such as amino acid transport
and RNA synthesis. LH may also induce ovulation by
transported to the granulose cells and aromatized to
stimulating a plasminogen activator that decreases tensile
estrogens (estrone and estradiol) by the action of strength of the follicle wall before follicular rupture occurs.
FSH.
FSH receptors exist primarily on the granulosa cell
membrane. In addition to stimulating LH receptors on this
cell membrane, FSH activates the aromatase and the 3β-‐
hydroxysteroid dehydrogenase enzymes within the cell by
increasing cAMP. FSH stimulation of isolated granulosa cells
in vitro produces only small amounts of estrogen; however,
when androgens or theca cells are added, large amounts of
estrogen are produced. These data support the two-‐cell
hypothesis of estrogen production. This hypothesis proposes
that LH acts on the theca to produce androgens
(androstenedione and testosterone), which are then
transported to the granulosa cells, where they are
aromatized to estrogens (estrone and estradiol) by the action
of FSH (see Fig. 4-‐13 ). The aromatase enzyme catalyzes this
The fundamental tenet of follicular development is the two-‐ conversion.
cell two-‐gonadotropin theory (Novak 7-‐63-‐65). This theory
states that there is a subdivision and compartmentalization Concomitant with increased estrogen production, mitosis is
of steroid hormone synthesis in the developing follicle. In stimulated in granulosa cells, augmenting cell number.
general, most aromatase activity (for estrogen production) is Estradiol and FSH receptor production is increased as well,
in the granulosa cells (N-‐7-‐66). Aromatase activity is maintain-‐ing intracellular cAMP levels as circulating FSH
enhanced by FSH stimulation of specific receptors on these decreases. In granulosa cells primed by exposure to large
cells (67, 68). However, granulosa cells lack several enzymes amounts of estradiol and FSH, LH acts synergistically with FSH
that occur earlier lin the steroidogenic pathway and require to increase LH receptors and induces luteinization of the
androgens as a substrate for aromatization. Androgens, in follicle, thereby increasing progesterone production.
turn, are synthesized primarily in response to LH, and the Premature delivery of LH will disrupt the process, resulting in
theca cells possess most of the LH receptors at this stage premature luteinization, whereas the capacity of the follicle
(67,68). Therefore, a synergistic relationship must exist: LH to respond to estrogen appears to determine whether it will
stimulates the theca cells to produce androgens (primarily mature or become atretic.
androstenedione), which, in turn, are transferred to the
granulosa cells for FSH-‐stimulated aromatization into LH also stimulates prostaglandin synthesis by intracellular
estrogens. These locally produced estrogens create a production of cAMP. Prostaglandin may play a role in follicle
microenvironment within the follicle that is favorable for rupture, since the prostaglandin content of preovulatory
continued growth and nutrition (69). Both FSH and local follicles increases at the time of the gonadotropin surge and
estrogen serve to further stimulate estrogen production, FSH may stimulate smooth muscle contraction. Progesterone
6 CMM
augments the activity of proteolytic enzymes, which act A diagram indicating where
together with prostaglandins to promote follicular activins and inhibins regulate
degradation and rupture. Plasminogen activator (PA) steroidogenesis
concentration also increases in the midcycle follicle, and its intragonadally.
action is enhanced by LH. Follicle rupture is blocked by In the ovary, activins are
administration of PA inhibitors in vivo. produced in the granulosa
cells, where they stimulate
At the level of the ovary, follicular recruitment and initial aromatase activity locally and
growth take place independently of gonadotropic hormones. inhibit progesterone
Animal studies have demonstrated that follicular production. Inhibin A and B
development can proceed to the antrum stage in the absence
stimulate progesterone and
of gonado-‐tropic influence. Although several hundred follicles
inhibit estradiol production in the ovarian follicle.
probably start to grow, the vast majority will degenerate and
no more than about 30 precursor follicles are likely to
become gonadotropic-‐dependent and be present at the INHIBIN
beginning of themenstrual cycle. Of these only a few under
physiologic conditions, with optimal FSH/LH stimulation, will
be selected for further growth and development. It is
believed that the rescue of follicles from degeneration by FSH
is achieved by reducing androgenicity and by maintaining a
predominately estrogenic environment. Initially this is
accompanied by FSH indirectly by stimulating activin
production and later by directly metabolizing LH-‐induced
thecal androgens to estrogens through stimulation of the
aromatizing process in granulosa cells. Lastly, the selection of
the dominant follicle is marked by its increased sensitivity to
FSH and its ability to produce a high concentration of
estrogen, as well as its ability to modulate gonadotropin ACTIVIN
secretion ( Fig. 4-‐14 ). The dominant follicle is usually
established by day 7 of the cycle.

ACTIVIN AND INHIBIN
Involment of HPO axis
• Closed-‐ loop negative
feedback system
• Inhibins inhibit FSH release
• Activins stimulate FSH release
The inhibins are stimulated in
granulosa cells by FSH and LH,
creating a closed-‐loop negative-‐ FOLLISTATIN
feedback system. The inhibins are
potent inhibitors of pituitary FSH.
The activins are produced in the
granulosa cells and stimulate the release of pituitary FSH
without affecting LH.

Involvement in ovarian steroid synthesis
• Inhibins-‐ stimulate progesterone and inhibit
estradiol production
• Activin-‐ inhibit progesterone and stimulate estradiol
production

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GONADAL STEROIDOGENESIS

Ovarian Steroids: Estrogen and Progesterone

Functions of Ovarian Steroids

Primordial germ cell maturation-‐ only 400-‐ 500 develop
to mature oocytes

Ovarian Development: Chronology

Steps of ovulation, beginning with dormant primordial
follicle that grows and matures and is eventually
released from the ovary into the fallopian tube
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fluid is stored. At ovulation the mature follicle ruptures and the
ovum surrounded by a glycoprotein layer (zona pellucida) and a
thick layer of cells (corona radiata) is expelled. Magnification: x65 at
6x7cm size. Magnification: x95 at 4x5 inch size.

As the oocyte matures, it acquires the following:
ü Zona pellucida-‐ a mucopolysaccharide coating that
allow spermatozoa only of the SAME species to
penetrate and fertilize the egg. As soon as a sperm
penetrates, cortical granules under the vitelline
membrane (which is just underneath the zona) are
released and block other spermatozoa.
ü Follicular fluid-‐ contains estrogen,androgens, proteins
such as inhibin, activin and folliculostatin that regulate
hormone synthesis in paracrine and autocrine fashion.
Some of these proteins also assist in follicle maturation.

The Dominant Follicle

Menstrual Cycle-‐ Relative pattern of ovarian and
uterine hormonal variation along the normal cycle

Stages of Ovulation

• At the start of each menstrual cycle, gonadal
hormones are low and has been declining since the
end of the luteal phase of the previous cycle.
Title: False-‐colour SEM of the surface of ovary
Caption: The ovary. False-‐colour scanning electron micrograph of • With the demise of the corpus luteum of the
the external surface of the ovary known as the germinal epithelium. previous cycle, FSH levels begin to rise and follicular
The swollen surface reflects the presence of a mature follicle recruitment of the next cycle begins. Under the
beneath, known as the Graafian follicle, in which the ovum is almost influence of FSH, these follicles grow and each
ready to be ejected into the Fallopian tube. The turgidness is caused
by an enlarged cavity in the follicle, the follicular antrum, in which
9 CMM
secrete increasing amounts of estradiol. The rising levels pick up at midluteal phase as a consequence
estrogen causes proliferation of the endometrium. of corpus luteum production (second estradiol
• Estrogen stimulate growth and differentiation of the peak).
functional layer of the endometrium and work • The decrease in LH frequency in the luteal phase is
synergistically with FSH for follicular development. due to the negative feedback effect of progesterone
• Rising levels of estradiol sends a negative feedback on the hypothalamus which decreases GnRH release.
the pituitary and hypothalamus resulting into (Increased β-‐endorphin levels probably mediates
inhibition of FSH release and FSH declines at this event). The decrease in LH amplitude is due to
midpoint of the follicular phase. Also, the granulose the negative feedback of progesterone on the
cells secrete inhibin which help suppress FSH. LH on pituitary.
the otherhand, is initially stimulated by secretion of • Estradiol and progesterone levels remain elevated
estrogen throughout the follicular phase. throughout the lifespan of the corpus luteum.
• The midpoint decline of FSH causes atresia of all However, its existence is dependent on LH. With
except one follicle-‐ the dominant follicle. The continuing decline in LH levels, there is demise of
dominant follicle produces about 80% of the daily the corpus luteum and sex steroid levels delines. In
estradiol production of 500µg. The rapid rise of 4-‐6 days after this fall menstruation ensues and the
estradiol and small amounts of progesterone from next cycle begins. If however, fertilization occurs,
the dominant follicle is the HPO signal that the there is rescue of the corpus luteum as a
follicle is ready to be ovulated. When a critical consequence of HCG production which acts as a
estradiol level isreached (200pg/ml or more for two surrogate for LH.
or more days), the initial negative feedback reverses
into a positive one and causes the LH and FSH surge Hormonal Changes in the Female Reproductive System
at midcycle. The LH surge initiates ovulation.
• At the end of the follicular phase just before
ovulation, FSH-‐induced receptors appear on the
granulose cells. LH stimulation modulates
progesterone secretion.
• LH surge initiates germinal vesicle disruption and
metaphase I is completed. The oocyte enters
metaphase II and the first polar body appears. (It is
only upon sperm penetration into the zona pellucida
when meiosis is completed and the second polar THE MENSTRUAL CYCLE
body is extruded). • The menstrual cycle is made up of two segments:
• Prior to rupture, LH stimulates synthesis of PGF2α The ovarian cycle and the endometrial cycle. The
and PGE and collagenase. FSH stimulates production ovarian cycle divided into the follicular and luteal
of plasminogen activator which converts phases whereas the endometrial is made up of the
plasminogen to plasmin, a proteolytic enzyme. proliferative and luteal phases. A normal menstrual
These facilitates follicular rupture and egg cycle lasts about 28 days +/-‐ 7 days with an
extrusion. average blood loss of about 20-‐60ml.
• After extrusion of the oocyte, there is a decrease in
follicular fluid , the follicular wall convolutes and THE OVARIAN CYCLE
there is a marked decrease in diameter and volume • The Follicular Phase is the time wherein hormonal
of the follicle. The granulosa cells become feedback ensures the development of a single
vascularized allowing LH to reach more receptors. dominant follicle which matures and is ovulated at
Both granulose and theca cells become luteinized midcycle. This phase is quite variable but on the
and acquire yellow coloration. average lasts from 10-‐14 days.
• Under LH, the corpus luteum produces significant • The Luteal Phase is the time from ovulation to onset
amounts of progesterone. Estradiol levels of menstruation and averages about 14 days.
meanwhile decreases just before ovulation and
continues to lower in the early luteal phase. Its
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THE ENDOMETRIAL CYCLE OVULATION OCCURS

• The endometrium has two layers-‐ stratum basale • 24hrs after the first estradiol peak
above the myometrium and stratum functionale • 32 hrs after the intial rise in LH
which is between the basale and the uterine lumen. • 12-‐16 hrs after peak LH levels in the serum
The basale is made up of primordial glands and
dense cellular stroma. It does not change
throughout the cycle and does not desquamate at
menstruation. The functionale is composed of the
narrow stratum compactum which is superficial and
made of the neck of endometrial glands plus dense
stromal cells and the broader stratum spongiosum
which is made up of glands, less denser stroma, and
a lot of interstitial tissues. The functionale grows
during the cycle and desquamates during the
menses.
• Rising LH levels
The Proliferative Phase stimulate an increase in cAMP. cAMP mediates
• starts at day 1 of the menses. After menstrual luteinization and resumption of meiosis, overcoming the
bleeding, the endometrium is only 1-‐2 mm thick and action of local inhibitors, luteinization inhibitor
is made up only of the basale and a part of the (LI) and oocyte maturation inhibitor (OMI). As
spongiosum. The proliferative phase is the time luteinization proceeds, progesterone levels rise,
when there is mitotic growth of the decidua enhancing the activity of proteolytic enzymes and
increasing follicle wall distensability. Prostaglandin
functionalis in response to increasing levels of
(PG) levels increase and, together with plasmin and
estrogen. There is growth of both glandular and collagenase, may serve to digest the follicle wall. The
stromal elements. From the early stages of this midcycle surge brings about completion of reduction
phase wherein narrow, straight and short division and formation of the first polar body (OB).
endometrial glands evolve, the glands become Midcycle FSH stimulates expansion of the cumulus and
increasingly tortuous and longer and assume a production of plasminogen activator (PA). Continued
pseudostratified appearance just prior to ovulation. enzymatic digestion results in follicle wall rupture.

Prostaglandins (PG) may stimulate contraction of smooth
The Secretory Phase muscle in the theca externa, causing oocyte expulsion.
• After ovulation when this phase ensues, the cellular Branching vessels penetrate the luteinized granulosa.
effects of progesterone appear. Glycogen-‐rich
vacuoles appear initially subnuclear (subnuclear CLINICAL GUIDELINES FOR NORMAL MENSTRUATION
vacuolization is the first histologic evidence of
progesterone but not necessarily ovulation) and
then progress towards the lumen. The glycogen
content is eventually released into the cavity.
Stroma become more edematous and vascular.
Several proteins are also produced by the
endometrium during this time as well as peptide
hormones, growth factors and prostaglandins. These
may have roles in decidualization should fertilization MENSTRUATION
occur. In the absence of blastocyst implantation and • Menstrual sloughing is initiated by enzymatic
HCG to maintain the corpus luteum, collapse and digestion of tissue which is brought about by matrix
fragmentation of endometrial glands set in. metalloproteinases (MMPs) produced by the
Inflammatory elements such as PMNs and endometrium upon withdrawal of progesterone.
monocytes infiltrate glands and stroma. There is also Coagulation occurs after this, initially with platelet
autolysis of the functionalis layer and desquamation plug formation followed by more organized
ensues. coagulation cascade. Thereafter, vasoconstriction of
blood vessel occurs and endometrial
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reepithelialization happens as estradiol levels pick

up.
• Desquamation largely occurs in the fundus, not in
the isthmic, cervical, and corneal areas. Surface
epithelial regeneration occurs as early as 36 hours
after onset of menses. This reepithelialization is
completed in about 48 hours.

Repair of desquamated endometrium occurs by two
processes:
1. Epithelial outgrowth from the mouths of the basal
glands
2. Ingrowth from endometrium in the cervical and
isthmic areas.

• Menstruation may also be the result of withdrawal
of sex steroids, leading to dissolution of integrity of
gap, intermediate and desmosomal junctions
between the glands, epithelial and stromal
elements.
• Menstruation is due to a combination of ischemia,
increases in IL-‐8, lysis from hydrolytic enzymes from
macrophages and loss of cell-‐cell-‐binding proteins
leading to superficial tissue shedding.
Reorganization and regeneration of endometrial
cells follow subsequently.

12 CMM

(Gyne) 1.2 Reproductive Endocrinology - CMM

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GYNECOLOGY

1.2: REPRODUCTIVE ENDOCRINOLOGY (ppt only)

peptides (Catheolamines, • Methyldopa blocks tyrosine hydroxylase and

The secretion of GnRH secretion by the hypothalamus is

LH/FSHà Induce immediate and transient FUNCTIONS: LH

THE ENDOMETRIAL CYCLE OVULATION OCCURS

reepithelialization happens as estradiol levels pick

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