PEDIATRIC UROLITHIASIS

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Ovarian Menstrual Cycles
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Objectives

• 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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Definition

• 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.

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Features 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

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Proliferative 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

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Secretory 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.

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The unique blood supply of the endometrium
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Menstrual cycle
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Endometrial histology
Proliferative phase
Secretory phase
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Premenstrual endometrium
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Menstruation

• 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.

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Endocrine 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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Ovulatory cycle
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Hypothalamus
Hypothalamus Pituitary Stalk Pituitary gland
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GnRH

• 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).

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GnRH

• 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

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GnRH 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
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Neural 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
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FSH 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.

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LH 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.

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Feedback 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
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Feedback 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

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Feedback 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.

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Patterns 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.
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Two 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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Oogenesis

• THE FOLLICULAR PHASE
• Recruitment of a Follicle Cohort
• Selection of the Dominant Follicle
• Growth of the Dominant Follicle
• OVULATION
• THE LUTEAL PHASE

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Oogenesis

• Primordial follicle
• Growing follicle
• Preantral follicle
• Antral follicle
• Mature Graafian follicle
• Ovulation
• Corpus luteum

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Oogenesis

• 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.

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Oogenesis

• 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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Oogenesis

• 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.

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Established 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
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Principal 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
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Principal 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
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Principal 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
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Mature 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.

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Ovulation

• 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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Corpus 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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