the cycle

The The Cycle Cycle

Steven L. Young MD, PhDSteven L. Young MD, PhDObstetrics & GynecologyObstetrics & GynecologyUNC School of MedicineUNC School of Medicine

MysteryMysteryMenstrualMenstrual

Mystery Cycle?Mystery Cycle?

Don’t Panic!

Overall ObjectivesOverall Objectives

1.1. Identify normal cycle Identify normal cycle characteristicscharacteristics

2.2. Understand the physiologic function Understand the physiologic function of the menstrual cycle.of 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.

Normal 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

% IN

CIDE

NCE

Menstrual 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


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.



Only seen in primatesOnly seen in primates ReproductionReproduction

Monthly 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 CycleFollicular Luteal

CYCLE DAYCYCLE DAY2 10 12 144 6 8 16 2818 2420 22 26

Endometrial Cycle

OvulationProliferative

Secretory


Synchronization

OvulationOvulation

OvaryOvary::

FollicularFollicular LutealLuteal

UteruUterus:s:

ProliferativeProliferative SecretorySecretory


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

Inhibinexternal genitalia, prostate

Testosterone

-

++

-

-+

TestosteroneTestis

oocyte

pituitarygonadotrophs

hypothalamus(arcuate nucleus)

Pulsatile GnRH

FSH (+LH)

LH

Inhi

bin

++

+

Theca Granulosa

Androgens

--

E2

+/-

uterus

+/-

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

Proliferative1. 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 Follicular Mid to Late Follicular Ovulation

Uterine Proliferative (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 25-28 Days 25-28

Ovarian Early Luteal Midluteal Late Luteal

Uterine Early Secretory

Mid Secretory

Late Secretory Decidua

Hormonal ’s

ing P, E2 & Inhibin

High P, E2 & Inhibin

ing E2, P, & Inhibin

ing FSH

ing hCG and P

Actions Endometrial Differentiation

Allow Embryo

Implantation

prepare for menses and recruit new follicular

cohort

Maintain CL P

production

Not Pregnant Pregnant

the cycle

Documents

lh release

hormone action

fsh productionreleased

fsh synthesis

lh receptor

direct action

sites of production

estrogen lh androgen