Physiology Of Physiology Of MenstruationMenstruation

Disusun Oleh:Nur Afiqah Binti Jasmi 11-2013-031

Luqman Hakim Bin Mohd Jais 11-2013-170Dokter Pembimbing:

dr Harianto Wijaya Sp.OG

Kepaniteraan Klinik Ilmu Obstetri & Ginekologi RSUD TarakanFakultas Kedokteran Ukrida

MENSTRUAL CYCLE

• Menstrual Cycle: 28 ± 7 days . Varied

• Menstrual flow:4 ± 2 days

• Hypothalamus-Pituitary-Ovary Axis

• Hormone Communication

HYPOTHALAMUS

Hypothalamus ----------------------------------------------> Circulating Hormones

Hypothalamus ------------------------------> Pituitary

Hypothalamus ------>Hypothalamus

Long Feedback Loop

Short Feedback Loop

Ultrashort Feedback Loop

REPRODUCTIVE FUNCTIONS OF THE HYPOTHALAMUSGonadotropin-Releasing Hormone• Decapeptide• From arcuate nucleus• Half life : 2-4 minutes • Gonadotropin-releasing hormone (GnRH) ->

controlling factor for gonadotropin secretion.• Kiss1 gene -> Kisspeptins -> GPR54

(receptor) -> Signaling GnRH & GAP secretion

Neuronal Body Neuronal Body

Pre-pro-GnRHPre-pro-GnRH

GnRH decapeptideGAP

GnRH decapeptideGAP

Portal VesselPortal Vessel

ProteolyticProteolytic

Nerve terminalNerve terminal

GnRH geneGnRH gene

GnRH Pulsatile Secretion

Continuous Exposure

Downregulation

GnRH receptor decrease

Intermittent Exposure

UpregulationAutoprime

GnRH receptor increase

Follicular Phase Luteal PhaseMid Follicular

Endogenous Opioids and Effects on GnRH

Opioid Endorphin ↑ Inhibit GnRH releases

Ovarian Sex Streoids

EndorphinPeak: Luteal PhaseNadir: Menses

PITUITARY

Gonadotrophs are specialized cell types of the anterior pituitary that synthesize and secrete LH and FSH

Gonadotrophs contain cell-surface GnRH receptors that mediate the action of GnRH.

Gonadotropin-Releasing Hormone Receptor

• Hypothalamic GnRH -> Pituitary -> GnRH type I receptor -> activation of Gq/11.

• PKC-, Ca2+-, and tyrosine kinase–dependent pathways.

• Type 2 receptors: Inhuman Primates

Identical α subunit

Gonadotropins Location of β-subunit gene

Size of β-subunit Half-life in serum

FSH Chromosome 117aa[*] 3-4h[†]

11p13

LH Chromosome 121aa 20 min[#]

19q13.3

hCG Chromosome 145aa 24h

19q13.3

Regulation of Circulating Levels of FSH & LH

Pituitary

Gonad Hormones

CarbohydratesResidue

Subunit α > β

InhibinActivinFollistatin

Autocrine/ParacrineMechanism

Sialic AcidhCG > FSH > LHslower clearance

OVARY

Adult OvaryAdult Ovary

Length: 2-5cmWidth: 1.5-3cm

Thickness: 0.5-1.5cmWeight: 5-10g

Length: 2-5cmWidth: 1.5-3cm

Thickness: 0.5-1.5cmWeight: 5-10g

Cortex: germinal epithelium, follicleMedulla: tissue, contractile cells,

interstitial cellsHilum : blood vessel, lymp, erves

Cortex: germinal epithelium, follicleMedulla: tissue, contractile cells,

interstitial cellsHilum : blood vessel, lymp, erves

Ovaries Functions

Production of oocytes

Production of steroid

and Peptide

Hormones

Embryology of

Ovary

Endoderm of yolk

sac

Coelemic Epithelial

cells

Mesenchymal Cells

Primordial Germs

Cells

Granulosa Cells

Ovarian Stroma

Primordial Cells

Oogonia

Primary Ooocyte

Primordial Follicle

Atretic

3rd week of gestation: Yolk Sac6th week of gestation: Migration into the gonadal ridge -> generate the primary sex cords .

Mitosis at Gonad

12th week of gestation

Meiosis

Surrounded by single layer of flattened granulosa cells

The number of oocytes in the ovary before and after birth and through Menopause.

Meiotic Division during Oocyte Maturation

Ovarian Follicular Development

Functional anatomy and developmental changes in the adult ovary during a ovarian cycle.

Steroidogenesis Across the Life Span

Childhood • 8 weeks' gestation: Ovary →estrogen • 2nd trimester: Gonadotropin ↑• The fetal hypothalamic-pituitary axis continues to mature

-> sensitive to estrogen and progesterone -> fetal gonadotropins fall to low levels prior to birth.

• Newborn: ↑ gonadotropins• Childhood: The hypothalamic-pituitary axis increased

sensitivity to negative feedback →↓FSH LH • ↑ FSH:LH ratio : premenarchal girl and postmenopausal

woman. 　 　　 　 　 　

Puberty • LH secretion ↑. Difference Day & Night• LH > FSH levels: Reproductive Years 　 　 　• ↑ LH & FSH → ↑estrogen : growth spurt, maturation of the

female internal and external genitalia, and development of a female habitus

• Activation of the pituitary-adrenal axis → adrenal androgen production→axillary and pubic hair (adrenache or pubarche).

Postmenopause

• Few follicles → ↓estrogen & inhibin → ↑LH and FSH → androstenedione → estrone but inadequate to protect against bone loss.

Variations in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during different life stages in the female.

E & P Receptor

Estrogen

Progesteron

+ ligand

FOLLICULAR PHASE

• 10–14 day• A series of sequential actions

of hormones and autocrine/paracrine peptides on the follicle

• Follicle destined to ovulate goes through a period of initial growth from a primordial follicle through the stages of the preantral, antral, and preovulatory follicle.

Primordial Follicle

Primordial follicle in the cortical stroma. A layer of flattened follicular epithelial cells surrounds the oocyte with its large nucleus and prominent nucleolus. The ooplasm is not stained

• The granulosa cells become cuboidal and increase in number to form a pseudostratified layer.

• The decline in luteal phase estrogen, progesterone, and inhibin-A production by the now-fading corpus luteum from the previous cycle

• The increase in FSH that stimulates this follicular growth.

• Hormone-mediated effects can be transmitted throughout the follicle.

• Oocyte begins secretion of an acellular coat known as the zona pellucida. 　 　 　 　

PreAntral Follicle

• The stroma differentiates into the theca interna, which is adjacent to the basal lamina, and the theca externa, which abuts the surrounding stroma

• Oocyte enlarges and is surrounded by a membrane, the zona pellucida

• Granulosa cells -> estrogens> androgens or progestins

Ovary—Secondary Follicle or Preantral Follicle

1 Follicular epithelium2 Zona pellucida3 Basal membrane4 Theca folliculi

Ovary—Secondary Follicle or Preantral Follicle

1 Beginnings of a follicular antrum2 Theca folliculi interna3 Theca folliculi externa4 Cortical stroma5 Primordial follicle

• Specific receptors for FSH are not detected on granulosa cells until the preantral stage, needed for androgen aromatase

• The administration of FSH will raise and lower the concentration of its own receptor on granulosa cells (up- and down-regulation)

Two-Cell Theory of Ovarian Steroidogenesis

Antral Follicle ( Tertiary Follicle)

• Follicular fluid begins to collect between the granulosa cells→ antrum.

• Rapid increase in follicular size • The granulosa cells surrounding the

oocyte are now designated the cumulus oophorus

• 1 Antrum folliculi • 2 Cumulus oophorus with oocyte• 3 Theca folliculi

LH Pulse Frequency:• Early follicular phase —90 minutes.• Late follicular phase —60–70 minutes.• Early luteal phase —100 minutes.• Late luteal phase —200 minutes.

LH Pulse Amplitude:• Early follicular phase —6.5 IU/L.• Midfollicular phase —5.0 IU/L.• Late follicular phase —7.2 IU/L.• Early luteal phase —15.0 IU/L.• Midluteal phase —12.2 IU/L.• Late luteal phase —8.0 IU/L.

Gonad Peptide Hormone

• Inhibin: Inhibitor of FSH secretion.

• Activin: Stimulates FSH release

• Follistatin : binding activin: Suppresses FSH activity

INHIBIN

2 Forms of Inhibin:• Inhibin A: Alpha-BetaA ( Corpus Luteum-Luteal Phase)• Inhibin B: Alpha-BetaB ( Granulosa Cells-Follicular

Phase )

Inhibin: block the synthesis and secretion of FSH, reduce the number of GnRH receptors present, promotes intracellular degradation of gonadotropins.

FSH - Inhibin — a reciprocal relationship Inhibin B: rises slowly but steadily, in a pulsatile fashion

(60–70 min periodicity) reaching peak levels in the early and midfollicular phases, a nadir in the midluteal phase.

Inhibin A: suppression of FSH to nadir levels during the luteal phase

ACTIVIN

• Activin : • Prior to ovulation: supress Progesteron production• Stimulate FSH release and GnRH receptor

number.• Circulating levels of activin increase in the late

luteal phase to peak at menses

3 Forms of Activin:• 　 　 　 　 Activin A: BetaA-BetaA• 　 　 　 　 Activin AB: BetaA-BetaB• 　 　 　 　 Activin B: BetaB-BetaB

Follistatin

• Follistatin playing a role by inhibiting activin and enhancing inhibin activity.

Selection Of Dominant Follicle

• The successful conversion to an estrogen dominant follicle marks the “selection” of a follicle destined to ovulate -> One Single Follicle Succeed ->

Dominant Follicle -> Estrogen• estrogen - FSH interaction (+ for maturing

follicle)• estrogen - pitutary interaction (- feedback)-> FSH ↓Other cells entered Apoptosis -> TNF -> inhibit

FSH stimulation , estradiol secretion

PreOvulatory / Graafian Follicle

• Fluid-filled antrum that is composed of plasma with granulosa-cell secretion

• The oocyte remains connected to the follicle by cumulus oophorus

• Estrogens - LH (+ feedback) -> Luteinization of the granulosa cells -> Progesterone & Prostaglandin -> Initiation of ovulation

• Plasminogen -> Proteolytic enzymes, plasmin

• Ovulation will occur in the single mature, Graafian follicle 10 to 12 hours after the LH peak or 34 to 36 hours after the initial rise in midcycle LH.

• Inhibin, Activin and follistatin, insulinlike growth factor (ILGF)-1, epidermal growth factor (EGF)/transforming growth factor (TGF)-α, TGF-β1, β-fibroblast growth factor (FGF), interleukin-1, tissue necrosis factor-α, OMI, and renin–angiotensin

Ovary—Graafian FollicleHuman follicles reach a

diameter of 20–25mm

1 Antrum folliculi 2 Cumulus oophorus 3 Granulosa epithelial cells4 Theca folliculi5 Radial corona cells

OVULATION

• Oocyte-cumulus is released from the follicle

• Toward the end of the follicular phase, estradiol levels increase dramatically

• Estradiol - Pituitary (+ Feedback)• Estradiol concentrations of 200

pg/mL for 50 hours →initiate a gonadotropin surge

• The mean duration of the LH surge is 48 hours

• Ovulation occurrs approximately 36 to 40 hours after the onset of the LH surge

• Gn surge -> Plasminogen activity ↑• Plasmin and collagenase-> follicular

wall thinning• Prostaglandin-> Ovary muscle

contraction• Extrusion of the oocyte only lasts a

few minutes

LUTEAL PHASE• The remaining -> corpus

luteum• granulosa / theca cells

proliferate + hypertrophy -> granulosa-lutein cells / smaller theca-lutein cells

• Basement membrane degenerates + vascularize -> Capillary invasion

• Progesterone Dominant -> 40 mg of progesterone per day

• Inhibin A -> low FSH level

Corpus Luteum

1 Granulosa lutein cells 2 Theca lutein cells3 Connective tissue of the theca folliculi

LUTEOLYSIS

• Luteal regression

• Blood supply diminishes

• E & P secretion drop

• Luteal cells apoptosis -> fibrotic -> corpus albicans

The Luteal-Follicular Transition

• Estradiol, progesterone, inhibin -> nadir• E & P decrease -> increasing GnRH

pusatile • Inhibin A decrease + increasing GnRH

pulsatile -> FSH > LH

UTERUS

• Decidua functionalis

-intermediate zone (stratum spongiosum)

-superficial compact zone (stratum compactum). • Decidua basalis is the deepest region of the endometrium

Proliferative Phase

• Early proliferative phase, the endometrium is relatively thin (1–2 mm).

• Initially straight, narrow, and short endometrial glands → longer structures.

• These proliferating glands have multiple mitotic cells

• Low columnar pattern → pseudostratified pattern before ovulation.

Proliferative Phase

• Proliferative phase: straight to slightly coiled, tubular glands are lined by pseudostratified columnar epithelium with scattered mitoses.

Secretory Phase

Early secretory phase: • 48-72 hours after

ovulation: Progesteron↑

• coiled glands lined by simple columnar epithelium

• glycogen containing vacuoles

• Apocrine secretion• Stroma edema

• Late secretory phase:

• serrated, dilated glands with intraluminal secretion are lined by short columnar cells.

• 2 days before menses: PMN infilitration→endometrial stroma collapse

• Decidua functionalis breakdown→menses

• Sex steroids withdrawal: spiral artery vascular spasm →endometrial ischemia.

• Lysosomes breakdown →proteolytic enzymes →promote local tissue destruction.

• Prostaglandin F2α → potent vasoconstrictor→ arteriolar vasospasm and endometrial ischemia. PGF2α also produces myometrial contractions

Menstrual Phase

Effects of Ovarian Steroids on Endometrium

Striking thickening of endometrial tissue. Stroma & epithelial proliferate rapidly.

inhibit or reverse proliferative action of estrogen. Differentiation of epthelial & stroma.