Download Ch7. Reproductive Physiology

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
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
-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
-pituitary releasing factor~pituitary H.
:GnRH~LH,FSH
CRH~ACTH
GHRH~GH
TRH~TSH
direct extension (through infundibular stalk)
~neurohypophtseal H. (posterior pituitary)
 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)
-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)
 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
 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)
-frequency & amplitude of pulsatile secretion
: throughout menstrual cycle, tightly regulated
: follicular phase-small amplitude
late follicular phase-frequency↑ ,amplitude↑
luteal phase-progress frequency↓, amplitude↓
 GnRH Agonist
-mechanism of action
:increase receptor affinity or decrease degradation
:initial release of gonadotropins
the secretion of pituitory store
continued activation: downregulation
 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
 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
: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
 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)
 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)
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)
: factor-breast manupulation, drugs, stress,
exercise, certain food
→ hormones
: secretory stimulation
-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)
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
 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.
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
: normal mestrual cycle
-cyclic hormone production
proliferation of the uterine lining for implantation
: disorder of the menstrual cycle
-pathologic state, infertility, miscarriage, malignancy
 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
 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
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
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
: normal menstrual cycle
-21~35 days
2 ~6 flow
20- 60 ml
 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
<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
<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 endometrial cell’s estrogen receptor concentration)
: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
: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 lymphocyte increase from vascualr system
-leukocyte :collapse stroma, onset of menstrual flow
<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
-after shedding, leaving the decidua basalis
: Prostaglandin F2a – vasoconstritor
myometrial consracton
→ decrease local uterine blood flow
expel sloughing endometrial tissue
 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
 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
: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)
 Meiotic arrest of oocyte and resumption
: meiosis – prophase
metaphase: leptotene
zygotene
pachytene
diplotene
diakinesis
anaphase
telophase
: begin at GA 8 weeks
: arrest
-oocyte maturation inhibitor (OMI)
‘ produced by granulosa cell
 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
<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>
: 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
: 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)
: 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
<ovulation>
: midcycle LH surge
- dramatic increase prostaglandin.proteolytic enzyme
- weaken the follicular wall and then ruptured
 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
- if pregnant, placental hCG stimulate the corpus
luteum to secrete progesterone
→ successful implantation