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Ch7. Reproductive Physiology. 부산백병원 산부인과 R2 서 영 진. Neuroendoclinology. Endoclinology -the study of hormone Neuroscience -the study of action of neurons the menstrual cycle is regulated through the feedback of hormones on the neural tissue of the central nervous system.

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ch7 reproductive physiology

Ch7. Reproductive Physiology

부산백병원 산부인과

R2 서 영 진

neuroendoclinology
Neuroendoclinology
  • Endoclinology

-the study of hormone

  • Neuroscience

-the study of action of neurons

the menstrual cycle is regulated through the

feedback of hormones on the neural tissue

of the central nervous system

anatomy
Anatomy
  • Hypothalamus

- at the base of the brain

above the optic chiasm

below the third ventricle

- connected directly to the pituitary gland

the source of many pituitary secretions

-3 zones: periventricular(adjacent to the third ventricle)

medial(primarily cell bodies)

lateral(primarily axonal)

 further subdivided into a nuclei

slide5
-multiple interconnections

:pituitary

limbic system(amygdala, hippocampus)

thalamus, pons

form feedback loop

-feedback

:long-input from circulating H.(androgen,estrogen)

short-pituitary H.

ultrashort-hypothalamic secretion, itself

slide6
-pituitary releasing factor~pituitary H.

:GnRH~LH,FSH

CRH~ACTH

GHRH~GH

TRH~TSH

direct extension (through infundibular stalk)

~neurohypophtseal H. (posterior pituitary)

slide8
Pituitary

-3 regions: anterior, intermediate, posterior

-anterior pituitary(adenohypophysis)

:embryologically from epidermal ectoderm from

an infolding of Rathke’s pouch

:not composed of neural tissue (not have direct

neural connections to the hypothalamus)

:no direct arterial blood supply

(portal vessels: rich capillary plexus)

slide9
-posterior pituiatry (neurohypophysis)

:direct neural connection to the hypothalamus

:blood supply (hypophyseal arteries)

-specific secretory cell

(hemotoxylin & eosin staining pattern)

:acidophilic~GH, prolactin, ACTH

basophilic~gonadotropins

neutral~TSH

reproductive hormone hypothalamus
Reproductive Hormone(Hypothalamus)
  • Gonadotropin-releasing hormones (GnRH)

:decapeptide

in the arcuate nucleus of the hypothalamus

:GnRH-secreting neuron project axons to the portal

vessels at the median eminence where GnRH is

secreted for delivery to the anterior pituitary

slide11
Pulsatile secretion

-continuous: decrease the number of gonadotroph

cell surface GnRH receptor

 downregulation

-pulsatile: increase its number of GnRH receptor

 upregulate, autoprime

-continual pulsatile secretion

:because of short half-life of GnRH (2~4 min)

(rapid proteolytic cleavage)

slide12
-frequency & amplitude of pulsatile secretion

: throughout menstrual cycle, tightly regulated

: follicular phase-small amplitude

late follicular phase-frequency↑ ,amplitude↑

luteal phase-progress frequency↓, amplitude↓

slide14
GnRH Agonist

-mechanism of action

:increase receptor affinity or decrease degradation

:initial release of gonadotropins

the secretion of pituitory store

continued activation: downregulation

slide15
GnRH antagonist

: competitive blockade of GnRH receptor

preventing stimulation by endogenous GnRH

: compare with GnRH agonist

reduce the time for therapy

:moreover, downregulation of GnRH receptor

loss of gonadotropin activity

slide16
Structure-Agonist

:GnRH is degraded by enzymatic cleavage between

its amino acids (5~6, 6~7, 9~10)

:substitution of amino acid 6 (Gly)

carboxyl terminus

long half life, increase affinity

constant GnRH exposuresdownregulation

slide17
:control ovulation induction cycles

treat precocious puberty

hyperandrogenism

leiomyoma, endometriosis

hormonally dependent cancers

  • Antagonist

:development-more difficult

:commercial antagonist-modification amino acid

1,2,3,6,10

slide18
Endogenous opioids and effects on GnRH

: endorphin, dynorphin- temperature, appetite

mood, behavior

enkephalin- autonomic nervous system

: endorphin level –peak in the luteal phase

nadir during menses

→ dysphoria in the premenstrual phase

reproductive hormone pituitary hormone secretion
Reproductive Hormone(Pituitary hormone secretion)
  • Anterior piuitary

1. Gonadotropins

: ovarian follicular stimulate gonadotroph cell

→produce FSH, LH

: similarity between FSH and LH

- indentical alpha subunit

differ only in the beta sulunit

(differ in carbohyrate content as a resiult of

posttranslation modificaton)

slide20
2. Prolactin

: 198-amino acid polypeptide

secreted by the lactotroph

the synthesis of milk by the breast

: under ‘tonic inhibition’ by dopamine

-decreased dopamine secretion or interrupts

of dopamine pathway

→prolactin secretion

(clinically, amenorrhea, galactorhhea,

hyperprolactinemia)

slide21
: factor-breast manupulation, drugs, stress,

exercise, certain food

: secretory stimulation hormones

-TRH, vasopressin, GABA, endorphin, VIP

3. TSH

: TRH (arcuate nucleus of the hypothalamus)

→ portal circulation → TSH release → T3,T4

(→ negative feedback to the TSH secretion)

slide22
4. ACTH

: CRH → ACTH → adrenal glucocorticoids

: diurnal variation (morning↑, late evening↓)

5. GH

: GHRH (tyroid hormone, glucocorticoid)

→ GH secretion (pulsatile, peak during sleep)

: bone mitogenesis, CNS functon,

body composition, cadiovascular function,

insulin regulation, ovarian function

slide23
Posterior pituitary

1. Oxytocin

: nine-amino acid peptide

by the paraventricular nucleus of hypothalamus

: uterine contraction during parturition

breast lactiferous duct myoepithelial contraction

during the milk letdown reflex

: sulking → thoracic nerve →spinal cord →

hypothalamus

: other- olfactory, auditory, visual, stimulate Cx, vag.

slide24
2. Arginine-vasopressin (AVP , ADH)

: in the supraoptic nuclei

: regulation of blood volume, pressure, osmolality

: specific receptor

-osmoreceptor (hypothalamus) ; 285mOsm/kg

baroreceptor (Lt atrium, carotid a. , aortic arch)

→respond to >10% blood vol. Change

- BP decrease → AVP→arteriolar vasoconstriction

, renal free water conservation→decrease the

blood osmolarity→ increase BP

menstrual cycle physiology
Menstrual Cycle Physiology

: normal mestrual cycle

-cyclic hormone production

proliferation of the uterine lining for implantation

: disorder of the menstrual cycle

-pathologic state, infertility, miscarriage, malignancy

slide27
Nomal menstrual cycle

: ovarian cycle- follicular & luteal phases

uterine cycle- proliferative & secretory phases

: follicular phase- hormonal feedback

mature at midcycle & prepared

for ovulation

10~14 (variable)

: luteal phase- ovulation~ the onset of mense

average length of 14 days

slide28
Hormonal variations

1. at the beginning of menstrual cycle, levels of

gonadal steroids are low

2. with the demise of the corpus luteum, FSH levels

begin to rise and cohort of growing follicle is

recruited.

these follicle- increasing levels of estrogen

stimulate Ut endometrial proliferation

slide29
3. estrogen ↑- negative feedback on pituitary FSH

secretion (midpoint of follicular phase)

LH level- initially decrease

increase dramatically in late

4. at the end of the follicular phase, FSH-incuced LH

receptors on granulosa cell modulate the secretion

of progesterone

5. after estrogenic stimulation, LH surge is triggered

ovulation- occurs within 24 to 36 hrs

transition to the luteal-secretory phase

slide30
6. before ovulation~ the midluteal phase: estrogen↓

rise again as a result of corrpus luteum secretion

7. progesterone- rise after ovulation

8. estrogen & progesterone levels remain elevated

through the lifespan of the corpus luteum and then

wane with its demise

slide31
: normal menstrual cycle

-21~35 days

2 ~6 flow

20- 60 ml

slide33
Uterus

-Cyclic changes of the endometrium

:by cyclic hormonal production of the ovaries

:histologic change-endometrial glnads

surrounding stroma

:decidua functionalis

-superficial 2/3(stratum compactum, spongiosum)

-proliferates and ultimately shed

:decidua basalis

-not proliferation but regeneration source

slide34
<Proliferative phase>

:after menses, desidua basalis is composed of

primordial glands & dense scant stroma

desidua functionalis-progressive mitotic growth

for implantation

response to estrogen level

:endometrial glands

straight, narrow, short → longer, tortous

cell- columnar → pseudostratified

stroma- dense compact

slide35
<Secretory phase>

:within 48 to 72 hrs following ovulation (cycle day14)

- onset of progesterone → secretory phase begin

- eosinophilic protein-rich secretory products

:response to progesterone & estrogen

(progesterone: progressive decrease in the endome-

trial cell’s estrogen receptor concentration)

slide36
:endometrial glands

-acid-Schiff positive staining, glycogen-containing

vacuoles

-cycle day 16: vacuoles appear subnuclearly

then, progress toward the lumen

cycle day 17: midportion nuclei

cycle day 19,20: apocrine secretion

postovulatory 6,7 day: maximal secretory activity

prepare implantation

slide37
:stroma

-unchanged until postovulatory 7 day

-progressive increase in edema

-spiral arteries → lengthen & coil

-day 24,eosinophilic staining in the perivascular area

(pseudodecidual)

-2 days prior to menses, polymorphonuclear lympho-

cyte increase from vascualr system

-leukocyte :collapse stroma, onset of menstrual flow

slide38
<Menses>

: in the absence of implantation

-ceases glandular secretion

breakdown of the decidua functionalis

shedding of this layer→ MENSES

-corpus luteum destruction: progesterone,estrogen↓

-spiral artery spasm, endometrial ischemia

breakdown fo lysosomes, proteolytic enzyme release

slide39
-after shedding, leaving the decidua basalis

: Prostaglandin F2a – vasoconstritor

myometrial consracton

→ decrease local uterine blood flow

expel sloughing endometrial tissue

slide40
Dating the endometrium

:the state of the endometrium corresponds to the

phase of the mensnstrual cycle

:more than 2-day lag time

-‘luteal phase defect’

-implantation failure, early pregnancy loss

:endometrial biopsy

-postovualtory 10~12 days

-at implantation, postovulatory 6~8day

slide41
Ovarian follicular development

;the number of oocyte

GA 20 weeks- 6~7 million

birth- 1~2 million

puberty- 300,000

→ release 400~500 during ovulation

slide42
:in human, oogonial formation or mitosis does not

occur postnatally

:in the fetus ~ until ovulation

-presist the diplotene resting stage

-synthesize DNA, proteins, mRNA

-diplotene stage: primordial follicle

(8~10 layer granulosa cells surround the oogonia)

slide43
Meiotic arrest of oocyte and resumption

: meiosis – prophase

metaphase: leptotene

zygotene

pachytene

diplotene

diakinesis

anaphase

telophase

slide47
: begin at GA 8 weeks

: arrest

-oocyte maturation inhibitor (OMI)

‘ produced by granulosa cell

slide48
Follicular development

: monthly recruitment of a cohort of follicle

release a single mature dominant follicle

<primordial follicles>

:initial recruitment & growth

-gonadotropin independent

the stimuli are unknown

:FSH-control of follicular differentiation & growth

gonadotripin dependent growth

:granulosa cell- multilayer of cuboidal cell

slide49
<preantral follicle>

: by the stimulus of FSH

: enlarging oocyte

: secretes a glycoprotein-rich substance

-zona pelucida (separates oocyte from surrounding

granulosa cells)

: theca cells in the stroma proliferate

: both cells type produce estrigen synergistically

<Two-cell two-gonadotropin theory>

slide51
: androgens roles

-low concentration: stimulate aromatase activity

high concentration: intense 5a-reductase

cannot be aromatized

: peripheral estrogen increase

-negative feedback: decrease FSH level

inhibin production

slide52
: progression of the follicular phase

→ FSH decrease → FSH binding advantage follicle

(greatest number of FSH recertors)

: in result, the single dominant follicle exist

the others are atresia

<preovulatory follicle>

: fluid-filled antrum (glanulosa cell secretion)

: oocyte connected to the follicle by a stalk

(cumulus oophorus)

slide53
: FSH – negative feedback by estrogen

LH – biphasic regulation by estrogen

low estrogen- inhibit LH

high estrogen- release LH (>48hrs, >200 pg/ml)

: a specific response- luteinization

production of progesterone

initiation of ovulation

: ovulation- 10~12 hrs after LH peak

34~36 hrs after initial rise

slide54
<ovulation>

: midcycle LH surge

- dramatic increase prostaglandin.proteolytic enzyme

- weaken the follicular wall and then ruptured

slide56
Luteal phase

: structure of corpus luteum

-membranous glanulosa cells remain, yellow (lutein)

, take up lipid→ corpora albicans

-secretion of progesterone→ endomerium change

-secretion of angiogenic factor (ex, EGF)

: hormonal function and regulation

-if pregnancy does not occur: FSH,LH ↓

inhibit the further development and recruitment of

additional follicle

slide57
- if pregnant, placental hCG stimulate the corpus

luteum to secrete progesterone

→ successful implantation