the cycle steven l. young md, phd obstetrics & gynecology unc school of medicine mystery...
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The The Cycle Cycle
Steven L. Young MD, PhDSteven L. Young MD, PhD
Obstetrics & GynecologyObstetrics & Gynecology
UNC School of MedicineUNC School of Medicine
MysteryMysteryMenstrualMenstrual
Mystery Cycle?Mystery Cycle?Mystery Cycle?Mystery Cycle?
Don’t Panic!
Overall ObjectivesOverall Objectives
1.1. Identify normal cycle Identify normal cycle characteristicscharacteristics
2.2. Understand the physiologic Understand the physiologic function of the menstrual cycle.function of the menstrual cycle.
3.3. Review the structure, sites of Review the structure, sites of production, action, and production, action, and physiologic function of major physiologic function of major reproductive hormones.reproductive hormones.
4.4. Understand how hormone action Understand how hormone action determines the menstrual cycle.determines the menstrual cycle.
Normal Cycle CharacteristicsNormal Cycle Characteristics
Interval: 24-35 days (mean: 28 days)Duration: 2-7 days (mean: 5 days)Volume: Mean of 35 ml (> 80 ml abnormal)Composition: Nonclotting blood,
endometrial debris, dead and living endometrial cells
22 24 26 28 30 32 34 36 38 40
2
4
6
8
10
12
14
DAYS
% INCIDENCE
Menstrual Cycle LengthMenstrual Cycle Length
Menstrual Cycle Length:Menstrual Cycle Length:mean, median, 5th and 95th percentile by mean, median, 5th and 95th percentile by
ageage
Mean MedianMeanMean MedianMedian
80
70
60
50
40
30
20
10
010 15 20 25 30 35 40 45 50 55 60
DAYS
CHRONOLOGICAL AGE
Overall ObjectivesOverall Objectives
1.1. Identify normal cycle characteristicsIdentify normal cycle characteristics
2.2. Understand the physiologic function of Understand the physiologic function of the menstrual cycle.the menstrual cycle.
3.3. Review the structure, sites of Review the structure, sites of production, action, and physiologic production, action, and physiologic function of major reproductive function of major reproductive hormones.hormones.
4.4. Understand how hormone action Understand how hormone action determines the menstrual cycle.determines the menstrual cycle.
Only seen in primatesOnly seen in primates
ReproductionReproductionMonthly FertilityMonthly Fertility
OvaryOvaryMonthly Mono-OvulationMonthly Mono-Ovulation
UterusUterusPreparation for Embryo ImplantationPreparation for Embryo Implantation
Synchronization of Ovary & UterusSynchronization of Ovary & Uterus
Why a Menstrual Cycle?Why a Menstrual Cycle?
Ovulation
Ovarian Cycle
Follicular Luteal
CYCLE DAYCYCLE DAY
2 10 12 144 6 8 16 2818 2420 22 26
Endometrial CycleEndometrial Cycle
OvulationProliferative
Secretory
CYCLE DAYCYCLE DAY2 10 12 144 6 8 16 2818 2420 22 26
SynchronizationSynchronization
OvulationOvulation
OvaryOvary::
FollicularFollicular LutealLuteal
UteruUterus:s:
ProliferativeProliferative SecretorySecretory
CYCLE DAYCYCLE DAY2 10 12 144 6 8 16 2818 2420 22 26
Overall ObjectivesOverall Objectives
1.1. Identify normal cycle characteristicsIdentify normal cycle characteristics
2.2. Understand the physiologic function of Understand the physiologic function of the menstrual cycle.the menstrual cycle.
3.3. Review the structure, sites of Review the structure, sites of production, action, and physiologic production, action, and physiologic function of major reproductive function of major reproductive hormones.hormones.
4.4. Understand how hormone action Understand how hormone action determines the menstrual cycle.determines the menstrual cycle.
The CharactersThe Characters
HormoneHormoneStructuralStructural
TypeType SourceSource TargetsTargets
GnRHGnRH Peptide Peptide (10 aa)(10 aa)
HypothalHypothalamusamus PituitaryPituitary
FSH & LHFSH & LH GlycoproteGlycoprotein Dimerin Dimer
PituitarPituitaryy
GonadGonad
EstrogenEstrogenProgesteronProgesteron
eeAndrogenAndrogen
SteroidSteroidGonadGonad
(+adrena(+adrenal)l)
Gonad, Gonad, Uterus, Uterus, Prostate, Prostate,
Ext.GenitaliExt.Genitaliaa
Hypoth & PitHypoth & Pit
InhibinInhibin GlycoproteGlycoprotein Dimerin Dimer GonadGonad Gonad, Gonad,
PituitaryPituitary
hCGhCGGlycoproteGlycoprote
ininDimerDimer
EmbryoEmbryo OvaryOvary
Reproductive Endocrine Circuits
hypothalamus
pituitary
ovary
GnRH
LHFSH
oocyte
Estradiol,Progesterone, & Inhibin
Uterus & Breast
sperm
hypothalamus
pituitary
Testis
GnRH
LHFSH
Testosterone& Inhibin
Prostate
GnRH
Decapeptide that stimulates LH Decapeptide that stimulates LH and FSH productionand FSH production
Released into portal blood Released into portal blood vessels for direct action on vessels for direct action on pituitary.pituitary.
Must be released in pulsatile Must be released in pulsatile fashion to stimulate LH and FSH fashion to stimulate LH and FSH synthesis and release.synthesis and release.
Hypothalamic-Pituitary Anatomy
LH & FSH Production Require Pulsatile GnRH
GonadotropinsGonadotropins FSH, LH, and hCGFSH, LH, and hCG
Glycoprotein heterodimersGlycoprotein heterodimers Share same alpha subunit with each other Share same alpha subunit with each other and TSH.and TSH.
Stimulate ovaryStimulate ovary FSH - folliclular development, estrogenFSH - folliclular development, estrogen LH - androgen, ovulation, progesteroneLH - androgen, ovulation, progesterone
LH (and probably FSH) are released in LH (and probably FSH) are released in pulses corresponding to GnRH pulses.pulses corresponding to GnRH pulses.
LH and hCG bind the LH receptor, but LH and hCG bind the LH receptor, but hCG has a much longer serum half-life. hCG has a much longer serum half-life.
Steroids: Estradiol & Progesterone Derived from C27 Cholesterol
Estradiol (C18) Causes endometrial proliferation
Feeds back to pituitary (low levels supress LH release, high levels trigger LH release)
Induces female secondary sexual characteristics
Breast development, body fat distribution
Progesterone (C21) Causes Endometrial Differentiation
Stops endometrial proliferation
Allows embryo implantation
High levels suppress pituitary FSH & LH
Steroid Inter-conversion
Progesterone Androstenedione
Pregneneolone
Estrone
DHEA-S
Cholesterol C27
17-OH-Preg
17-OH-Prog
Testosterone Estradiol
Aldosterone
Cortisol
C21 C19
C18
Inhibins
TGF- family glycoprotein heterodimer produced primarily in ovarian granulosa cells (Inhibin B) and in luteal cells (Inhibin A)
Inhibits pituitary FSH secretion, also functions in ovary
Sertoli Leydig
pituitarygonadotrophs
sperm
hypothalamus(arcuate nucleus)
Pulsatile GnRH(portal vessels)
LH (+FSH)
FSH
Inhibin
external genitalia, prostate
Testosterone
-
++
-
-
+
Testosterone
Testis
oocyte
pituitarygonadotrophs
hypothalamus(arcuate nucleus)
Pulsatile GnRH
FSH (+LH)
LH
Inhi
bin
++
+
Theca Granulosa
Androgens
--
E2
+/-
uterus
+/-
Overall ObjectivesOverall Objectives
1.1. Identify normal cycle characteristicsIdentify normal cycle characteristics
2.2. Understand the physiologic function of Understand the physiologic function of the menstrual cycle.the menstrual cycle.
3.3. Review the structure, sites of Review the structure, sites of production, action, and physiologic production, action, and physiologic function of major reproductive function of major reproductive hormones.hormones.
4.4. Understand how hormone action Understand how hormone action determines the menstrual cycle.determines the menstrual cycle.
Key Events in CycleKey Events in Cycle
Menstruation (shedding of Menstruation (shedding of endometrium) defined as day 1endometrium) defined as day 1
Proliferative or Follicular PhaseProliferative or Follicular Phase
OvulationOvulation (about d14.5 of cycle) (about d14.5 of cycle)
Secretory or Luteal PhaseSecretory or Luteal Phase
Endometrium receptive for embryo Endometrium receptive for embryo implantation (d20-24 of cycle).implantation (d20-24 of cycle).
Key Points: d1-5 of cycle Ovarian view = Early Follicular
1. FSH drives Growth of a follicular cohort2. Growing follicles: FSHR, E2, & inhibin &
vascularity of theca layer
Uterine view = Menstrual / Early Proliferative
1. E2 causes endometrial proliferation and hypertrophy (from 1mm single layer to 4-5 mm at ovulation).
Pituitary View1. FSH rises beginning a few days before d1
due to falling levels of inhibin A and P and E2 from failing corpus luteum
Key Points: d5-13 of cycle
Ovarian view = Late Follicular Phase. By day 5-7 falling FSH levels result in selection of the follicle most sensitive to FSH (dominant follicle). The dominant follicle produces increasing amounts of E2 and is destined to ovulate and while all other follicles become atretic.
Uterine view = Proliferative Phase. Increasing E2 throughout the proliferative phase causes endometrial proliferation and hypertrophy (from 1mm single layer to about 4-5 mm).
Pituitary View. As inhibin and E2 rise, FSH is decreased. At moderate E2 levels there is increased LH storage but inhibited release.
Key Points: d14 (Ovulation) Ovarian view
The dominant follicle has been able to make more and more E2 since acquiring increased FSH receptors and later LH receptors. A small amount of progesterone production stimulates a significant FSH surge which helps to further increase E2. In response to the LH surge, the oocyte is released and completes meiosis I. After ovulation the granulosa cells and some thecal cells form a corpus luteum which secretes E2 and P.
Pituitary View. High E2 (>200 pg/mL) sustained over > 50 hrs causes massive release of LH.
Key Points: d15-28 Ovarian view = Luteal phase.
Corpus luteum has lifespan of 14 +/- 2 days unless rescued by logarithmic increases in hCG. CL produces E + P + inhibin. CL fails and increasing FSH recruits a new follicular cohort.
Uterine view = Secretory. P causes a series of morphological and biochemical changes (differentiation) to allow the endometrium to become receptive to embryo implantation. Without pregnancy, P + E fall with CL atresia, resulting in sloughing of the functionalis layer of endometrium - menstruation. (day 1 of new cycle)
Pituitary View. CL-derived E + P + inhibin suppress FSH production. As CL fails, FSH rises.
Menstrual Cycle: menses to ovulation
Days 1-4 Days 5-13 Days 13-14
Ovarian Early FollicularMid to Late Follicular
Ovulation
UterineProliferative (menstrual)
Proliferative Proliferative
Hormonal low E2 & Inhibin, ing FSH
ing E2 & Inhibin, ing FSH
High E2, LH surge
Actions
Follicle development and
endometrial proliferation
Selection of dominant follicle and endometrial
proliferation
Oocyte maturation & Release
Ovarian Steroidogenesis: 2 Cells, 2 Gonadotropins
ThecaCell
GranulosaCell
B.M.Stroma Follicle
FSH-RLH-R
Cholesterol
Androgens
Estrogens
Early to Mid-Follicular
Ovarian Steroidogenesis: 2 Cells, 2 Gonadotropins
ThecaCell
GranulosaCell
B.M.Stroma Follicle
FSH-RLH-R
Cholesterol
Androgens
Estrogens+ Progesterone
Late Follicular through Ovulation
LH-R
Cholesterol
Menstrual Cycle: ovulation to menses
Days 15-19 Days 20-24 Days 25-28Days 25-
28
Ovarian Early Luteal Midluteal Late Luteal
UterineEarly
SecretoryMid
SecretoryLate
SecretoryDecidua
Hormonal ’s
ing P, E2 & Inhibin
High P, E2 & Inhibin
ing E2, P, & Inhibin
ing FSH
ing hCG and P
ActionsEndometrial
Differentiation
Allow Embryo
Implantation
prepare for menses and recruit new follicular
cohort
Maintain CL P
production
Not Pregnant Pregnant