PHYSIOLOGY OF THE NORMAL MENSTRUAL CYCLE

Daisy N. Punzalan, M.D.

Menstruation endometrial tissue

shedding with hemorrhage that is dependent on sex steroid hormonedirected changes in blood flow in the spiral arteries

Spiral arteries arise from the arcuate

arteries which are branches of the uterine vessels that lie in the myometrium

HYPOTHALAMIC-PITUITARYOVARIAN-ENDOMETRIAL AXIS
The success of human reproduction depends on the highly coordinated interactions between the hypothalamus, anterior pituitary gland, ovaries & uterine endometrium that occur during a normal menstrual cycle.

GnRH (gonadotropin-releasing hormone) the hypothalamic hormone that controls the gonadotropic function of the anterior pituitary Pituitary Gonadotropins: 1. FSH (follicle-stimulating hormone) 2. LH (luteinizing hormone)

The Ovarian Cycle

2 Phases Follicular (Preovulatory) ovarian phase estradiol 17 is secreted 2 M oocytes birth 400, 000 follicles onset of puberty 400 follicles reproductive life Oocytes partly control the early steps in follicular development

FSH required for further devt of the large antral follicles. It rises during the late luteal phase of the previous cycle (Selection window) > - FSH receptors > aromatize the thecal cellderived androstenedione into estradiol - the exclusive site of its receptor expression is the granulosa cells - a drop on FSH is responsible for the failure of other follicles to reach preovulatory status the GRAAFIAN FOLLICLE STAGE

LH stimulates thecal cell production of androstenedione and metabolizes to estradiol The requirement for thecal cells that respond to LH and granulosa cells that respond to FSH represents the two gonadotropins two cell hypothesis for estrogen biosynthesis

Ovulation
Predicted by the onset of the gonadotropin surge resulting from increasing secretion of estrogen by preovulatory follicles (34-36 hours prior to ovum release) LH peak occurs 10-12 hrs. before ovulation

The Ovarian Cycle

Luteal (Postovulatory ) Ovarian Phase progesterone is secreted

Luteinization corpus luteum

develops from the remains of the dominant folicle or graafian follicle

Just after ovulation, estrogen levels decrease followed by a secondary rise that reaches a peak production of 0.25 mg/ day of 17 beta estradiol in the midluteal phase Ovarian production of progesterone peaks at 25-50 mg/day during the midluteal phase

If pregnancy occurs, the corpus luteum continues production of progesterone in response to embryonic hcG. In the absence of pregnancy, it will regress 9-11 days after ovulation. The regression of the corpus luteum and drop in circulating steroids during the late luteal phase leads to MENSTRUATION.

Hormonal Regulation of the Endometrium Estrogen the essential hormone signal in which most events in the nornal menstrual cycle depend. 17 estradiol the most biologically potent naturally occuring estrogen secreted by the granulosa cells of the dominant ovarian follicle and luteinized granulosa cells of the corpus luteum - involves 2 receptors: ER and ER

Estradiol 17 promotes the perpetuation of estrogen action & promotes the responsiveness of that tissue to progesterone - promotes growth of the endometrium esp. the glandular epithelial cells

Hormonal Regulation of the Endometrium

Progesterone enters cell by diffusion and in responsive tissues becomes associated with progesterone receptors - has two isoforms: PR-A and PR-B

Progesterone decreases the synthesis of estrogen receptor molecules - increases the rate of enzymatic inactivation of estradiol 17 estradiol dehydrogenase - increase sulfurylation of estrogen estrogen sulfotransferase

The Endometrial Cycle

The endometrium is regenerated during each ovarian-endometrial cycle. The superficial 2/3 of the endometrium is shed and regenerated almost 400x during the reproductive lifetime of most women.

2 Phases:
Proliferative (Preovulatory) Endometrial Phase
Early Phase endometrium is thin, usually less then 2 mm Late Phase endometrium thickens

2 Phases:
Secretory (Postovulatory) Endometrial Phase
Early Phase dating of the endometrium is based on the histology of the gladular epithelium Mid to Late Phase dating of the cycle relies on the changes seen in the endometrial stroma

After ovulation, the estrogen primed endometrium responds to rising levels of progesterone causing accumulation of glycogen in the basal portion of the glandular epithelium, creating subnuclear vacuoles and pseudostratification > 1st sign of ovulation

The secretory phase is highlighted by the continuing growth and development of the spiral arteries, lengthen at a rate that is appreciably greater than the rate of increase in endometrial thickness leading to even greater coiling of the already spiraling vessels. As the regression of the endometrium occur, the coiling becomes sufficiently severe that resistance to blood flow is increased strikingly causing hypoxia of the endometrium. The resultant stasis is the primary cause of endometrial ischemia and then tissue degeneration leading to menstruation.

Period of Vasoconstriction most striking and constant event preceding the onset of menstruation - serves to limit blood loss during menstruation - e.g. prostaglandins, vasoactive peptides( endothelins )

Late Premenstrual Phase - infiltration of the stroma by polymorphonuclear leukocytes giving a pseudoinflammatory appearance to the tissue and initiating extracellular matrix breakdown of the functionalis layer leading to MENSTRUATION.

Menstruation

-is the periodic discharge of blood, mucus, and cellular debris from the uterine mucosa

Severe coiling

stasis

hypoxia of the endometrium

vasodilatation

intense vasoconstriction

relaxation

hemorrhage

Role of Prostaglandins & Vasoactive peptides

Prostaglandin PGF2 vasoconstriction of the endometrial spiral arteries -causes myometrial contractions & uterine ischemia PGE2 & PGI2 - vasodilation

Vasoactive Peptides Endothelin-1 a potent vasoconstrictor Enkephalinase degrades endothelin-1 PTH-rP a vasorelaxant

Origin of Menstrual Blood

Both arterial and venous origin, but arterial bleeding is greater Rupture of an arteriole of a coiled artery with consequent formation of hematoma Leakage through a spiral artery Tissue autolysis

Clinical Aspects of Menstruation

Menarche 12 to 13 years of age Interval 28 days Duration 4 to 6 days Amount 25-60 ml blood loss 0.4-1 mg of iron loss