The Cycle

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The Cycle
Mystery
Menstrual

• Steven L. Young MD, PhD
• Obstetrics Gynecology
• UNC School of Medicine

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Mystery Cycle?
Dont Panic!
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Overall Objectives

1. Identify normal cycle characteristics
2. Understand the physiologic function of the
   menstrual cycle.
3. Review the structure, sites of production,
   action, and physiologic function of major
   reproductive hormones.
4. Understand how hormone action determines the
   menstrual cycle.

4
Normal Cycle Characteristics

• Interval 24-35 days (mean 28 days)
• Duration 2-7 days (mean 5 days)
• Volume Mean of 35 ml (gt 80 ml abnormal)
• Composition Nonclotting blood, endometrial
  debris, dead and living endometrial cells

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Menstrual Cycle Length
14
12
10
INCIDENCE
8
6
4
2
22
24
26
28
30
32
34
36
38
40
DAYS
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Menstrual Cycle Lengthmean, median, 5th and
95th percentile by age
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Overall Objectives

1. Identify normal cycle characteristics
2. Understand the physiologic function of the
   menstrual cycle.
3. Review the structure, sites of production,
   action, and physiologic function of major
   reproductive hormones.
4. Understand how hormone action determines the
   menstrual cycle.

8
Why a Menstrual Cycle?

• Only seen in primates
• Reproduction
• Monthly Fertility
• Ovary
• Monthly Mono-Ovulation
• Uterus
• Preparation for Embryo Implantation
• Synchronization of Ovary Uterus

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Ovarian Cycle
Ovulation
Luteal
Follicular
CYCLE DAY
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Endometrial Cycle
Ovulation
Secretory
Proliferative
CYCLE DAY
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Synchronization
Ovary Follicular Luteal
Uterus Proliferative Secretory
Ovulation
CYCLE DAY
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Overall Objectives

1. Identify normal cycle characteristics
2. Understand the physiologic function of the
   menstrual cycle.
3. Review the structure, sites of production,
   action, and physiologic function of major
   reproductive hormones.
4. Understand how hormone action determines the
   menstrual cycle.

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The Characters
Hormone Structural Type Source Targets
GnRH Peptide (10 aa) Hypothalamus Pituitary
FSH LH Glycoprotein Dimer Pituitary Gonad
Estrogen Progesterone Androgen Steroid Gonad (adrenal) Gonad, Uterus, Prostate, Ext.Genitalia Hypoth Pit
Inhibin Glycoprotein Dimer Gonad Gonad, Pituitary
hCG Glycoprotein Dimer Embryo Ovary
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Reproductive Endocrine Circuits
hypothalamus
hypothalamus
GnRH
GnRH
pituitary
pituitary
Estradiol, Progesterone, Inhibin
LH
FSH
LH
FSH
Uterus Breast
Testis
Prostate
ovary
sperm
oocyte
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GnRH

• Decapeptide that stimulates LH and FSH production
• Released into portal blood vessels for direct
  action on pituitary.
• Must be released in pulsatile fashion to
  stimulate LH and FSH synthesis and release.

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Hypothalamic-Pituitary Anatomy
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LH FSH Production Require Pulsatile GnRH
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Gonadotropins FSH, LH, and hCG

• Glycoprotein heterodimers
• Share same alpha subunit with each other
• and TSH.
• Stimulate ovary
• FSH - folliclular development, estrogen
• LH - androgen, ovulation, progesterone
• LH (and probably FSH) are released in pulses
  corresponding to GnRH pulses.
• LH and hCG bind the LH receptor, but hCG has a
  much longer serum half-life.

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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

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Steroid Inter-conversion
Pregneneolone
17-OH-Preg
C21
C19
Progesterone
Estrone
17-OH-Prog
C18
Testosterone
Estradiol
Cortisol
Aldosterone
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Inhibins

• TGF-b 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

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hypothalamus (arcuate nucleus)
-
Pulsatile GnRH (portal vessels)

pituitary gonadotrophs
-
-
FSH
LH (FSH)
external genitalia, prostate


Inhibin
Sertoli Leydig
Testosterone
sperm
Testis
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hypothalamus (arcuate nucleus)
/-
Pulsatile GnRH

pituitary gonadotrophs
-
/-
FSH (LH)
LH
Inhibin
E2


Theca
uterus
Androgens
oocyte
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Overall Objectives

1. Identify normal cycle characteristics
2. Understand the physiologic function of the
   menstrual cycle.
3. Review the structure, sites of production,
   action, and physiologic function of major
   reproductive hormones.
4. Understand how hormone action determines the
   menstrual cycle.

25
Key Events in Cycle

• Menstruation (shedding of endometrium) defined as
  day 1
• Proliferative or Follicular Phase
• Ovulation (about d14.5 of cycle)
• Secretory or Luteal Phase
• Endometrium receptive for embryo implantation
  (d20-24 of cycle).

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Key Points d1-5 of cycle

• Ovarian view Early Follicular
• ? FSH drives Growth of a follicular cohort
• Growing follicles ? FSHR, E2, inhibin
  vascularity of theca layer
• Uterine view Menstrual / Early Proliferative
• ? E2 causes endometrial proliferation and
  hypertrophy (from 1mm single layer to 4-5 mm at
  ovulation).
• Pituitary View
• FSH rises beginning a few days before d1 due to
  falling levels of inhibin A and P and E2 from
  failing corpus luteum

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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.

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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 (gt200 pg/mL) sustained over gt 50 hrs
  causes massive release of LH.

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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.

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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 D 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
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Ovarian Steroidogenesis 2 Cells, 2 Gonadotropins
Early to Mid-Follicular
B.M.
Follicle
Stroma
FSH-R
LH-R
Theca Cell
Granulosa Cell
Estrogens
Cholesterol
Androgens
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Ovarian Steroidogenesis 2 Cells, 2 Gonadotropins
Late Follicular through Ovulation
B.M.
Stroma
Follicle
LH-R
FSH-R
LH-R
Theca Cell
Granulosa Cell
Estrogens Progesterone
Cholesterol
Androgens
Cholesterol
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Menstrual Cycle ovulation to menses
Not Pregnant
Pregnant
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 Ds ?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