understand the hypothalmo-pituitary-ovarian axis Understand the ovarian/menstrual cycles with the hormonal interaction in the normal subject. Understand.

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

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.

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

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

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.

Secretory phase

The unique blood supply of the endometrium

Menstrual cycle

Endometrial histology

Proliferative phase Secretory phase

Premenstrual endometrium

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.

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

Endocrine control of menstruation

Ovulatory cycle

HypothalamusHypothalamus

Hypothalamus

Pituitary Stalk

Pituitary gland

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).

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

GnRH gene productGnRH gene productGnRH gene is 5 kb on Ch 8p

Precursor peptide (Pre-pro-GnRH)

Signal peptideGnRH

ProteolyticGAP

23 aa 10 aa 3 aa 56 aa

Stimulates

FSH/LH

Inhibits

PRLNB: Mutation in prohormone convertase 1 (PC1) gene results in insulin resistance

Neural control of GnRHArcuate venteromedial nucleus

High Amplitude

Follicular phase Luteal phase

NB: A critical GnRH pulse frequency and amplitude is needed for proper menstruation

HighFrequency

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.

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.

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 17β 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

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

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.

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.

Two cell hypothesis (Short 1963)

LH

FSH

Theca cell

Granulosa cell

Cholesterol

AD Te

AD Te

cAMP

cAMP

E1 E2

Two hormones

LH

FSH

Two cells

Theca cell

Granulosa cell

Two products

E1

E2

Oogenesis

THE FOLLICULAR PHASE – Recruitment of a Follicle Cohort – Selection of the Dominant Follicle– Growth of the Dominant Follicle

OVULATION

THE LUTEAL PHASE

Oogenesis

Primordial follicle Growing follicle

– Preantral follicle– Antral follicle

Mature Graafian follicle

Ovulation Corpus luteum

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.

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.

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.

Established and Putative Intraovarian Regulators

  Insulin-Like Growth Factor System  IGF-I  IGF-II  IGF binding proteins  Inhibin/Activin Systems  Inhibin  Activin  Follistatin  Interleukin-1 System  Interleukin-1  Interleukin-1 receptor antagonist  IL-1 binding protein (IL-1 receptor type II)  

Other Growth Factors  EGF/TGFα

  TGFβ1, TGFβ2  NGF

  aFGF, bFGF  VEGF  TNFα

  Other Peptidergic Factors  Ovarian renin angiotensin

system  VIP

  Oxytocin  Endothelin

Principal Actions of Intraovarian Regulators

Insulin-like growth factor-I   Follicle-stimulating hormone (FSH) amplification  Follicular growth  Follicular selection

  Transforming growth factor-α   Follicular maturation  Oocyte maturation  Cellular differentiation  Potentiation of gonadotropin action  Regulation of apoptosis

Principal Actions of Intraovarian Regulators Transforming growth factor-β1   Follicular rupture inhibition  Follicular differentiation

  Basic fibroblast growth factor   Apoptosis inhibition  Regulation of folliculogenesis

  Activin   Oocyte maturation  Follicular differentiation  Early embryogenesis  Regulation of steroidogenesis

Principal Actions of Intraovarian Regulators

Interleukin-1   Ovulation induction  Glycolysis  Glucose transport

  Tumor necrosis factor-α   Inhibits steroidogenesis  FSH antagonist  Induces apoptosis/luteolysis  Ovulation inhibition

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.

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.

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 LH+7, levels > 10 ng/ml indicate proper ovulation.

Ten days post ovulation the corpus luteum begins to decline unless hCG appears.