PHYSIOLOGY OF PHYSIOLOGY OF THE MENSTRUAL THE MENSTRUAL

CYCLECYCLE

Quoted with modification from Dr Salwa Quoted with modification from Dr Salwa NeyaziNeyazi

King Saud UniversityKing Saud University

NORMAL MENSTRUAL CYCLENORMAL MENSTRUAL CYCLEWhat is the mean duration of the MC?What is the mean duration of the MC?

Mean 28 days (only 15% of ♀)Mean 28 days (only 15% of ♀)

Range 21-35Range 21-35

What is the average duration of menses?What is the average duration of menses?

3-8 days3-8 days

What is the normal estimated blood loss?What is the normal estimated blood loss?

Approximately 30 mlApproximately 30 ml

When does ovulation occur?When does ovulation occur?

Usually day 14Usually day 14

36 hrs after the onset of mid-cycle LH surge36 hrs after the onset of mid-cycle LH surge

NORMAL MENSTRUAL CYCLENORMAL MENSTRUAL CYCLE

What regulates the phases of the MC & ovulation?What regulates the phases of the MC & ovulation?

Interaction between hypothalamus, pituitary & Interaction between hypothalamus, pituitary & ovariesovaries

What is the mean age of menarche & menopause?What is the mean age of menarche & menopause?

Menarche 12.7Menarche 12.7

Menopause 51.4 Menopause 51.4

HYPOTHALAMIC- PITUITARY- OVARIAN AXISHYPOTHALAMIC- PITUITARY- OVARIAN AXIS

PHASES OF THE MENSTRUAL CYCLE PHASES OF THE MENSTRUAL CYCLE

Ovulation divides the MC into two phasesOvulation divides the MC into two phases::

1-FOLLICULAR PHASE1-FOLLICULAR PHASE -Begins with menses on day 1 & ends with -Begins with menses on day 1 & ends with

ovulation.ovulation.

▲ ▲RECRUITMENTRECRUITMENT FSH FSH maturation of a cohort of ovarian maturation of a cohort of ovarian follicles follicles ““recruitmentrecruitment”” only one reaches maturityonly one reaches maturity

FOLLICULAR PHASEFOLLICULAR PHASE

MATURATION OF THE FOLLICLE MATURATION OF THE FOLLICLE (FOLLICULOGENESIS)(FOLLICULOGENESIS)

♥ ♥ FSH FSH primordial follicleprimordial follicle (oocyte arrested in the diplotene stage of the 1(oocyte arrested in the diplotene stage of the 1stst

meiotic division surrounded by a single layer of meiotic division surrounded by a single layer of granulosa cells)granulosa cells)

1ry follicle 1ry follicle (oocyte surrounded by a single layer of granulosa (oocyte surrounded by a single layer of granulosa

cells basement membrane & thica cells)cells basement membrane & thica cells)

2ry follicle or preantral follicle 2ry follicle or preantral follicle (oocyte surrounded by zona pellucida , several (oocyte surrounded by zona pellucida , several

layers of granulosa cells & thica cells) layers of granulosa cells & thica cells)

FOLLICULOGENESIS (2)FOLLICULOGENESIS (2)

tertiary or antral follicletertiary or antral follicle

2ry follicle accumulate fluid in a cavity 2ry follicle accumulate fluid in a cavity ““antrumantrum”.”.

The oocyte is in eccentric positionThe oocyte is in eccentric position

surrounded by granulosa cells surrounded by granulosa cells ““cumulous cumulous oophorusoophorus””

FOLLICULOGENESIS (2)FOLLICULOGENESIS (2)

SELECTIONSELECTION ♥ ♥Selection of the dominant follicle occurs Selection of the dominant follicle occurs

days days 5-75-7 ♥ ♥It depends on:- It depends on:- - The intrinsic capacity of the follicle to- The intrinsic capacity of the follicle to synthesize estrogensynthesize estrogen -High est./and. ratio in the follicular fluid-High est./and. ratio in the follicular fluid ♥ ♥As the follicle matures As the follicle matures estrogen estrogen FSH FSH -ve feed back on the pituitary-ve feed back on the pituitary the follicle the follicle with the highest No. of FSH receptors will with the highest No. of FSH receptors will continue to thrivecontinue to thrive ♥ ♥ The other follicles The other follicles ““that were recruitedthat were recruited”” will will become atreticbecome atretic

♥ ♥ FSH ACTIONSFSH ACTIONS -Recruitement -Recruitement -Mitogenic effect -Mitogenic effect No. of granulosa cells No. of granulosa cells FSH receptorFSH receptor -Stimulates aromatase activity -Stimulates aromatase activity conversion conversion

of of androgens androgens estrogens estrogens ““estrone & estradiolestrone & estradiol”” - - LH receptors LH receptors ♥ ♥ ESTROGENESTROGEN Acts synergistically with FSH to Acts synergistically with FSH to - induce LH receptors- induce LH receptors - induce FSH receptors in - induce FSH receptors in

granulosagranulosa & thica cells& thica cells♥ ♥ LH LH thica cells thica cells uptake of cholesterol & LDL uptake of cholesterol & LDL androstenedione & testosteroneandrostenedione & testosterone

FOLLICULOGENESIS FOLLICULOGENESIS (3)(3)

OTHER FACTORS THAT PLAY A ROLE IN OTHER FACTORS THAT PLAY A ROLE IN FOLLICULOGENISISFOLLICULOGENISIS

-INHIBIN -INHIBIN Local peptide in the follicular fluidLocal peptide in the follicular fluid -ve feed back on pituitary FSH secretion-ve feed back on pituitary FSH secretion Locally enhances LH-induced androstenedione Locally enhances LH-induced androstenedione

production production

FOLLICULOGENESIS FOLLICULOGENESIS (3)(3)

-ACTIVIN-ACTIVIN Found in follicular fluidFound in follicular fluid Stimulates FSH induced estrogen productionStimulates FSH induced estrogen production gonadotropin receptorsgonadotropin receptors androgenandrogen No real stimulation of FSH secretion in vivo (bound No real stimulation of FSH secretion in vivo (bound

to protein in serum) to protein in serum)

PREOVULATORY PERIODPREOVULATORY PERIOD

♥ ♥ NEGATIVE FEEDBACK ON THE PIUITARYNEGATIVE FEEDBACK ON THE PIUITARY

-- estradiol & inhibin estradiol & inhibin -ve feed back on pituitary -ve feed back on pituitary FSHFSH

-This mechanism operating since childhood-This mechanism operating since childhood

♥ ♥ POSITIVE FEEDBACK ON THE PITUITARYPOSITIVE FEEDBACK ON THE PITUITARY estradiol estradiol (reaching a threshold concentration(reaching a threshold concentration) )

++ve feed back on the pituitary ve feed back on the pituitary (facilitated by low (facilitated by low

levels of progestrone)levels of progestrone) LH surge LH surge secretion of secretion of progestroneprogestrone

Operates after pubertyOperates after puberty +ve feed back on pituitary +ve feed back on pituitary FSH FSH

PREOVULATORY PERIODPREOVULATORY PERIOD

LH SURGELH SURGE

Lasts for Lasts for 48 hrs 48 hrs Ovulation occurs after Ovulation occurs after 36 hrs36 hrs Accompanied by rapid fall in estradiol levelAccompanied by rapid fall in estradiol level Triggers the resumption of meiosisTriggers the resumption of meiosis Affects follicular wall Affects follicular wall follicular rupture follicular rupture Granulosa cells Granulosa cells lutenization lutenization progestrone synthesis progestrone synthesis

OVULATIONOVULATION

The dominant follicle protrudes from the ovarian The dominant follicle protrudes from the ovarian cortexcortex

Gentle release of the oocyte surrounded by the Gentle release of the oocyte surrounded by the cumuluscumulus

granulosa cellsgranulosa cells

Mechanism of follicular ruptureMechanism of follicular rupture 1-1- Follicular pressure Follicular pressure Changes in composition of the antral fluid Changes in composition of the antral fluid

colloidcolloid osmotic pressureosmotic pressure

OVULATIONOVULATION

2-Enzymatic rupture of the follicular wall2-Enzymatic rupture of the follicular wall LH & FSH LH & FSH granulosa cells granulosa cells production of production of

plasminogen activatorplasminogen activator plasmin plasmin fibrinolytic activity fibrinolytic activity break down of break down of

follicular wallfollicular wall LH LH prostglandin E prostglandin E plasminogen activator plasminogen activator PG F2PG F2αα lysosomes under follicular wall lysosomes under follicular wall

LUTEAL PHASELUTEAL PHASE

LASTS 14 days LASTS 14 days

FORMATION OF THE FORMATION OF THE CORPUS LUTEUMCORPUS LUTEUM

After ovulation the point of rupture in the follicular After ovulation the point of rupture in the follicular wall sealswall seals

Vascular capillaries cross the basement Vascular capillaries cross the basement

membrane & grow into the granulosa cells membrane & grow into the granulosa cells availability of LDL-cholesterolavailability of LDL-cholesterol

LH LH LDL binding to receptors LDL binding to receptors 33αα OH steroid dehydrogenase activity OH steroid dehydrogenase activity progesterone progesterone

LUTEAL PHASELUTEAL PHASE

Marked Marked in progesterone secretion in progesterone secretion Progesterone actions:Progesterone actions: -Suppresses follicular maturation on the-Suppresses follicular maturation on the ipsilateral ovaryipsilateral ovary -Thermogenic activity -Thermogenic activity basal body temp basal body temp -Endometrial maturation-Endometrial maturation Progesterone peak 8 days after ovulation Progesterone peak 8 days after ovulation (D22 MC)(D22 MC) Corpus luteum is sustained by Corpus luteum is sustained by LHLH It looses its sensitivity to gonadotropins It looses its sensitivity to gonadotropins luteolysis luteolysis estrogen & progesterone level estrogen & progesterone level desquamation of the desquamation of the

endometrium endometrium ““mensesmenses””

LUTEAL PHASELUTEAL PHASE

estrogen & progestrone estrogen & progestrone FSH & LH FSH & LH The new cycle starts with the beginning of The new cycle starts with the beginning of

mensesmenses If pregnancy occurs If pregnancy occurs hCG secretion hCG secretion maintains maintains

the the

corpus luteum corpus luteum

ENDOMETRIAL CHANGES DURING THE ENDOMETRIAL CHANGES DURING THE MENSTRUAL CYCLEMENSTRUAL CYCLE

1-Basal layer of the endometrium1-Basal layer of the endometrium

-Adjacent to the myometrium-Adjacent to the myometrium

-Unresponsive to hormonal stimulation-Unresponsive to hormonal stimulation

-Remains intact throughout the menstrual -Remains intact throughout the menstrual cyclecycle

2-Functional layer of the endometrium2-Functional layer of the endometrium

Composed of two layers:Composed of two layers:

-Zona compacta -Zona compacta superficial superficial

-Spongiosum layer -Spongiosum layer

ENDOMETRIAL CHANGES DURING THE MENSTRUAL ENDOMETRIAL CHANGES DURING THE MENSTRUAL CYCLECYCLE

1-Follicular /1-Follicular /proliferative phaseproliferative phase

Estrogen Estrogen mitotic activity in the glands & stroma mitotic activity in the glands & stroma endometrial thickness from 2 to 8 mmendometrial thickness from 2 to 8 mm

2-Luteal /2-Luteal /secretory phasesecretory phase

Progesterone Progesterone - Mitotic activity is severely restricted- Mitotic activity is severely restricted

-Endometrial glands produce then -Endometrial glands produce then secretesecrete

glycogen rich vacuolesglycogen rich vacuoles

-Stromal edema-Stromal edema

-Stromal cells enlargement-Stromal cells enlargement

-Spiral arterioles develop, lengthen & coil -Spiral arterioles develop, lengthen & coil

MENSTRUATIONMENSTRUATION

Periodic desquamation of the endometriumPeriodic desquamation of the endometrium The external hallmark of the menstrual cycleThe external hallmark of the menstrual cycle Just before menses the endometrium is infiltrated Just before menses the endometrium is infiltrated

with leucocyteswith leucocytes Prostaglandins are maximal in the endometrium Prostaglandins are maximal in the endometrium

just before menses just before menses Prostaglandins Prostaglandins constriction of the spiral constriction of the spiral

arterioles arterioles ischemia & desquamation ischemia & desquamation

Followed byFollowed by arteriolar relaxation, bleeding & arteriolar relaxation, bleeding & tissue breakdowntissue breakdown

HYPOTHALAMIC ROLE IN THE MENSTRUAL HYPOTHALAMIC ROLE IN THE MENSTRUAL CYCLECYCLE

The hypothalamus secretes GnRH in a pulsatile The hypothalamus secretes GnRH in a pulsatile fashionfashion

GnRH activity is first evident at pubertyGnRH activity is first evident at puberty Follicular phase GnRH pulses occur Follicular phase GnRH pulses occur hourlyhourly Luteal phase GnRH pulses occur every Luteal phase GnRH pulses occur every 90 minutes90 minutes Loss of pulsatility Loss of pulsatility down regulation of pituitary down regulation of pituitary

receptors receptors secretion of gonadotropins secretion of gonadotropins Release of GnRH is modulated by Release of GnRH is modulated by ––ve feedback by:ve feedback by: steroidssteroids gonadotropinsgonadotropins Release of GnRH is modulated by external neural Release of GnRH is modulated by external neural

signalssignals