Ch7. Reproductive Physiology

부산백병원 산부인과R2 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 exposuresdownregulation

: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 : 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)

→

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 endome- trial 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 lympho- cyte 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