Title: PEDIATRIC UROLITHIASIS
1Ovarian Menstrual Cycles
2Objectives
- understand the hypothalmo-pituitary-ovarian axis
- Understand the ovarian/menstrual cycles with the
hormonal interaction in the normal subject. - Understand the clinical significance and
implication in different aspect of gynecological
abnormalities and treatments
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4Definition
- Menstruation is Greek word that means toxin. It
is periodic uterine blood loss during
reproductive years of women. It is the red badge
of femininity.
5Features of menstruation
- Two types ovular or true menstruation and
anovular or false menstruation. - Two phases proliferative phase and secretory
phase. - The mean duration of the flow is 5 ? 3 days and
the average menstrual blood loss is 50 ml (20-80
mls). - The cycle is 28 ? 7 days.
- The mean age of menarche is 12.7 years
6Proliferative phase
- This phase lasts from the first day of menses
until ovulation - During this phase the endometrium (zona
functionalis) proliferates under the effect of E2
IGF-1 - Characteristics
- Variable length
- Low BBT
- Developing ovarian follicles
- Estrogen production (G-cells)
- Vascular growth of the endometrium
7Secretory phase
- This phase Extend from ovulation until the onset
of the next menses. - During this phase the endometrium show secretory
changes under the effect of ?4p. - Characteristics
- Constant length 14 days
- High BBT
- Formation of corpus luteum
- The endometrium show tortuous secretory glands
full of glycogen in preparation for nidation.
8The unique blood supply of the endometrium
9Menstrual cycle
10Endometrial histology
Proliferative phase
Secretory phase
11Premenstrual endometrium
12Menstruation
- The endometrium is divided into two zones the
basal one does not share in menstruation but it
the regenerative layer and the functional zone
that is shed during menstruation. - Progesterone withdrawal brings neutrophil
accumulation that dissociate the endometrial
stroma and the release of PGF2-? that cause
vasospasm of the contraction cone of Markee - The necrosed segment of the endometrium is washed
out during menstruation.
13Endocrine control of menstruation
- For proper menses to occur there should be a nice
integration between the hypothalamus, pituitary,
ovary and responsive uterus as well as a patent
effluent genital tract. - Hormones integrated
- GnRH
- FSH/LH
- E2/ ?4p
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15Ovulatory cycle
16Hypothalamus
Hypothalamus Pituitary Stalk Pituitary gland
17GnRH
- Hypothalamic control of gonadotropin secretion is
exerted via the release of gonadotropin-releasing
hormone .GnRH is a small peptide consisting of 10
amino acids (decapeptide). GnRH neurons migrate
into the brain from the embryonic olfactory
placodes, where they are first observed, to reach
the locations they will occupy during adult life
(hypothalamus). - GnRH is known to release both LH and FSH
-
- both LH and FSH are released in a pulsatile
rather than a continuous fashion. Each pulse of
LH consists of the abrupt release of the hormone
from the gonadotrope into the peripheral
circulation, followed by an exponential decline
representative of the hormone's half-life.
Pulsatile gonadotropin release is not the result
of an intrinsic property of the anterior
pituitary gland but is causally related to the
pulsatile release of GnRH (the GnRH pulse
generator).
18GnRH
- Only intermittent GnRH administration produces
sustained increases in both gonadotropins
continuous exposure, even to high doses of GnRH,
rapidly produces a desensitization of the
gonadotrope, resulting in a lowering of LH and
FSH release and the arrest of reproduction
function -
- A high GnRH pulse frequency favors LH synthesis
and release, but a low GnRH frequency favors FSH
synthesis and secretion
19GnRH gene product
Precursor peptide (Pre-pro-GnRH)
23 aa 10 aa 3 aa
56 aa
Proteolytic
Stimulates FSH/LH
Inhibits PRL
NB Mutation in prohormone convertase 1 (PC1)
gene results in insulin resistance
20Neural control of GnRH
High Amplitude
High Frequency
GnRH
Follicular phase
Luteal phase
NB A critical GnRH pulse frequency and amplitude
is needed for proper menstruation
21FSH receptors
- FSH-R are found primarily on granulosa cells
- FSH stimulates follicular growth (gametokinetic)
- FSH stimulates aromatase enzyme system in the
granulosa cells and hence estrogen production - Granulosa cells acquire LH receptors just before
ovulation.
22LH receptors
- LH-R are found on theca cells at all stages of
the cycle and on granulosa cells just before
ovulation - LH stimulates androgen production by theca cells
- When sufficient number of LH-R are acquired on
granulosa cells, LH stimulates luteinization and
progesterone production.
23Feedback Regulation of Gonadotropin secretion
the major feedback loop is inhibitory (negative
feedback loop) steroid hormones (estradiol and
progesterone) secreted by the target organ (the
ovary) feed back to the hypothalamic-hypophyseal
unit to adjust GnRH and gonadotropin secretion
Estradiol 17ß is a potent physiologic inhibitor
of GnRH and of gonadotropin secretion. levels
of LH and FSH during the follicular phase are
characteristically determined by the changes in
estradiol concentrations that accompany
maturation of the follicle. As circulating
estradiol levels increase, gonadotropin
concentrations decrease
24Feedback Regulation of Gonadotropin secretion
- The estradiol negative feedback loop acts to
decrease LH secretion mainly by controlling the
amplitude of the LH pulse. Thus, as the
follicular phase progresses, LH pulse amplitude
declines. LH pulse frequency during the
follicular phase (at intervals of 60 to 100
minutes), suggesting that estradiol does not
particularly affect LH pulse frequency
25Feedback Regulation of Gonadotropin secretion
- During the estrogenic stage or follicular phase,
pulses of high frequency but of low amplitude are
seen during the progesterone stage or luteal
phase, there is a great reduction in the
frequency of the LH pulse, with pulse intervals
of 200 minutes or more. This decreased pulse
frequency is accompanied by a significant
increase in pulse amplitude.
26Patterns of pulsatile luteinizing hormone (LH)
secretion during the human menstrual cycle. (A)
Note the high frequency of pulsatile LH release.
(B) Note the reduction in pulse frequency, with a
corresponding increase in pulse amplitude.
27Two cell hypothesis (Short 1963)
Two hormones LH FSH Two cells Theca
cell Granulosa cell Two products E1 E2
Theca cell
Cholesterol
LH
cAMP
AD Te
Granulosa cell
AD Te
FSH
cAMP
Aromatization
E1 E2
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29Oogenesis
- THE FOLLICULAR PHASE
- Recruitment of a Follicle Cohort
- Selection of the Dominant Follicle
- Growth of the Dominant Follicle
- OVULATION
- THE LUTEAL PHASE
30Oogenesis
- Primordial follicle
- Growing follicle
- Preantral follicle
- Antral follicle
- Mature Graafian follicle
- Ovulation
- Corpus luteum
31Oogenesis
- Primordial follicle
- An oocyte arrested in in the diplotene stage of
first meiotic prophase surrounded by a single
layer of granulosa cells - Initial follicular growth is independent of
hormone - The oocyte stock at the beginning of reproductive
life is 360,000.
32Oogenesis
- Preantral follicle
- An oocyte surrounded by the ZP and several layers
of granulosa cells and theca cells - FSH rescue some preantral follicles from atresia
and stimulate their growth, this may span more
than one cycle - FSH induces aromatization of thecal androgen in
the granulosa cells - Estrogen stimulates more follicular growth and
induces more FSH-R on granulosa cells.
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34Oogenesis
- Antral follicle
- Fluid accumulates in between granulosa cell
(Call-Exner) that coalese to form the antrum - Follicle destined to become dominant secretes
more estrogen that induces more FSH-R. - Dominant follicle continues to grow in spite of
declining level of FSH due to high receptor
content - Other follicles fail to do so and testosterone
accumulates to bring their atresia.
35Established and Putative Intraovarian
Regulators Insulin-Like Growth Factor
System IGF-I IGF-II IGF binding
proteins Inhibin/Activin Systems Inhibin Act
ivin Follistatin Interleukin-1
System Interleukin-1 Interleukin-1 receptor
antagonist IL-1 binding protein (IL-1 receptor
type II)
Other Growth Factors EGF/TGFa TGFß1,
TGFß2 NGF aFGF, bFGF VEGF TNFa Other
Peptidergic Factors Ovarian renin angiotensin
system VIP Oxytocin Endothelin
36Principal Actions of Intraovarian Regulators
Insulin-like growth factor-I Follicle-stimulati
ng hormone (FSH) amplification Follicular
growth Follicular selection Transforming
growth factor-a Follicular maturation Oocyte
maturation Cellular differentiation Potentiati
on of gonadotropin action Regulation of
apoptosis
37Principal Actions of Intraovarian Regulators
Transforming growth factor-ß1 Follicular
rupture inhibition Follicular
differentiation Basic fibroblast growth
factor Apoptosis inhibition Regulation of
folliculogenesis Activin Oocyte
maturation Follicular differentiation Early
embryogenesis Regulation of steroidogenesis
38Principal Actions of Intraovarian Regulators
Interleukin-1 Ovulation induction Glycolysis
Glucose transport Tumor necrosis
factor-a Inhibits steroidogenesis FSH
antagonist Induces apoptosis/luteolysis Ovulat
ion inhibition
39Mature Graafian follicle
- This is the follicle of the month destined to
ovulate - The capacity of this follicle to aromatize is
vast. - When the follicle reaches maturity 18-20 mm, the
estrogen level is of magnitude -200 pg/ml for 50
hours- to trigger LH surge and ovulation follows
12 hours after the peak.
40Ovulation
- LH surge triggers ovulation, it is a slow process
and involves enzymatic digestion of the
follicular wall - LH surge
- Resumption of meiosis
- Luteinization of granulosa cells
- Prostaglandin synthesis
- Mid-cycle rise of FSH is progesterone dependant
and loosens the oocyte in its bed so it becomes
free floating in the antral fluid - It is the secondary oocyte and first polar body
that come out at ovulation.
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42Corpus luteum
- The corpus luteum is formed after ovulation
under tonic effect of LH - Granulosa layer is invaded by blood vessels after
breakdown of the membrana limitans. Granulosa
cells increase in size accumulate lutein and
secrete progesterone. - Progesterone peaks at LH7, levels gt 10 ng/ml
indicate proper ovulation. - Ten days post ovulation the corpus luteum begins
to decline unless hCG appears.
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