Physiology of Menstruation

Janice M. Bernal-Lacuna, MD, FPOGS, FPSREI

Menstrual Cycle

Consequence of interactions between the hypothalamo-pituitary axis, the ovary and the uterus.

Ovary – active role Hypothalamus, pituitary -

permissive

Hypothalamo-pituitary-ovarian axis

hypothalamus

pituitary

ovary uterus

GnRH

FSH, LH

EstrogenProgesterone

GnRH

Peptide hormone High molecular weight of 200,000 –

300,000 daltons Binds to specific receptors on the

surface of the anterior pituitary stimulating the synthesis and release of LH and FSH

NeuroanatomyHypothalamus GnRH production

anterior hypothalamusmedial basal hypothalamus

arcuate nucleus

Pituitary Neurohypophysis

median eminenceinfundibular stalkposterior lobe

Adenohypophysisanterior lobe

Neuroanatomy Arcuate nucleus Arcuate nucleus

tuberoinfundibular tract median eminence

Arcuate nucleus tuberoinfundibular tract pituitary portal vessels anterior lobe

Pituitary neurohypohyseal capillary plexus hypothalamus

GnRH

Secreted in a pulsatile manner Half-life of 2-4 minutes Amplitude and frequency varies

throughout the menstrual cyclefollicular – 1 pulse/hrluteal – 1 pulse/ 2-3 hrs

Pulsatile GnRH gonadotrophin surge Increasing or decreasing the frequency,

or if given continuously will inhibit the gonadotrophin surge because the receptors are saturated

Anovulation and amenorrhea

GnRH secretion is regulated by ovarian steroids and the pituitary gonadotrophins

GnRH

GnRH analogues

GnRH agonists Longer half life Giving it once will cause a flare

effect gonadotrophin surge Giving it continuously will saturate

the receptors causing inhibition of gonadotrophin release desensitization or down-regulation

Side-effects: hypoestrogenic state

Use of GnRH analogues

Stimulation Delayed puberty Induction of ovulation

• Suppression• Precocious puberty• Endometriosis• Breast cancer• Uterine leiomyoma• Ovarian androgen excess

GnRH anatagonists

Nal-Glu directly inhibits ovulation Affects LH more than FSH,

decreases estradiol levels IVF

GnRH

Secretion is regulated by: Stimulatory and inhibitory feedback

effects of ovarian steroid hormones Inhibitory feedback of gonadotropins FSH

and LH Inhibition by GnRH itself Inhibition by neurotransmitters and

neuromodulators

Gonadotrophins: FSH and LH

Glycoproteins of high molecular weight 37,000 and 28,000 daltons respectively

Similar alpha-subunit with HCG and TSH

Luteinizing hormone Acts primarily on the theca cells to induce

steroidogenesis specifically androgens

Receptors exist in both theca cells (in all stages of the cycle) and in the granulosa cells (after follicular maturation)

Induce ovulation by stimulating a plasminogen activator that decreases the tensile strength of the follicular wall

LH acts with FSH and induces luteinization of the follicle, increasing progesterone production from the corpus luteum

Follicle stimulating hormone

Receptors are found primarily on the granulosa cells

Main function is to stimulate follicular growth

It stimulates the production of LH receptors on the granulosa cell

2 cell hypothesis of estrogen production – LH acts on theca cells to produce testosterone and androsteinedione, which are then transported to the granulosa cells where they are aromatized to estadiol and estrone by the action of FSH

Other factors affecting the HPO axis

Neurotransmitters Neuromodulators Brain peptides Ovarian peptides Growth factors

Neurotransmitters

Dopamine and norepinephrine Serotonin

Affected by stress and emotions Secreted by nerve cells

Dopamine and Norepinephrine

Tyrosine – precursor hypothalamus Dopamine - suppresses prolactin

and GnRH release Norepinephrine – stimulates GnRH

release

Serotonin

Tryptophan – precursor Stimulates the release of prolactin

from the pituitary which has an inhibitory effect on GnRH release

Neurotransmitters

Methyldopa – can block the synthesis of dopamine and norepinephrine

Reserpine and chlorpromazine - interfere with binding and storage

Tri-cyclic antidepressants – inhibit reuptake

Propranolol, haloperidol – block the receptors

Neuromodulators

Affect the actions of neurotransmitters

Opioids Prostaglandin Catechol estrogen

Opioids

Beta-endorphins Hypothalamus and pituitary Increase prolactin inhibits GnRH

decrease in LH Estrogen and progesterone increase

beta endorphins decreased frequency of GnRH pulses in the luteal phase

Prostaglandins

Administration of prostaglandin E2 increases GnRH in the portal blood

Assist in follicular rupture by facilitating proteolytic enzyme activity in the follicular walls

Potent effects on oviductal motility, help regulate myometrial contractility

The use of prostaglandin inhibitors can abolish LH surge

Catechol Estrogen

hypothalamus Inhibits tyrosine hydroxylase and

competes with methyl transferase enzyme

Affects dopamine and epinephrine No evidence that it affects

reproductive function

Brain peptides

Neuropeptide Y – stimulates pulsatile release of GnRH

Angiotensin II – affects dopamine and norepinephrine in the hypothalamus affecting prolactin and gonadotrophin release, and it has a local effect on the pituitary

Somatostatin – hypothalamic peptide which inhibits GH, prolactin and TSH release

Ovarian functions and control mechanism

Endocrine and gametogenic functions

Hormogenesis and folliculogenesis

Ovarian steroids

Estradiol – maturing follicle, 0.1 to 0.5 mg/day, highest before ovulation

Progesterone – corpus luteum, 0.5 to 4mg mg follicular phase, 20 to 30 mg luteal phase

Androstenedione – stroma, 1-2 mg/day Others – pregnenolone, 17-hydroxyprogesterone, testosterone,

DHEA and estrone

Ovarian steroid

Extraovarian interconversion Adipose tissue: androstenedione is

peripherally converted to estrone

Ovarian steroid transport and metabolism

Sex-hormone binding globulin (SHBG) – binds testosterone and estradiol

Corticosteroid-binding globulin (CBG) – binds cortisol, corticosterone and progesterone

95% of steroids are bound SHBG are increased by estrogen, obesity

and hyperthyroidism SHBG are lowered by androgens and

hypothyroidism

Non-steroidal hormone production

Activin– stimulates FSH release, progesterone production, promotion of folliculogenesis, prevents premature leuteinization

Inhibin – inhibits FSH release and oocyte maturation, stimulates thecal androgen production

Follistatin – inhibits FSH synthesis and secretion

Growth Factors

Insulin-like growth factors IGF-I and IGF-II from granulosa cells with receptors in both

theca and granulosa cells enhances steroidogenesis

Transforming growth factor and epidermal growth factor From theca cells Inhibit granulosa cell differentiation and

follicular cell steroidogenesis

folliculogenesis

Recruitment Selection Dominance Ovulation

Recruitment

End of the cycle – decrease in estrogen and progesterone

FSH level increases A group of follicles (cohort) is stimulated Small antral follicle with low threshold to

FSH will produce estrogen Granulosa cell proliferation End of cycle to day 5-7 of present cycle

Selection

Dominant follicle has the lowest threshold to FSH, has the greatest number of FSH receptors, with the greatest capacity for estrogen production

Negative feedback of estrogen other follicles become atretic

Dominant follicle become the Graafian follicle

Formation of LH receptors on the dominant follicle

Dominance

Dominant follicle produces estrogen even if FSH levels are decreasing

Enlarging antrum and proliferation of granulosa and theca cells

Peak estrogen level is reached 24-36 hours prior to ovulation

Gonadotropin surge (more of LH)

Ovulation

LH surge Resumption of meiosis allowing the

oocyte to undergo final maturation Luteinization of granulosa and theca

cells with increased production of progesterone

Follicle rupture with extrusion of a mature oocyte

Luteinization

The dominant follicle reorganizes Granulosa cells, the surrounding theca-

interstitial cells and the vasculature become the corpus luteum

Progesterone production LDL – substrate Dependent on LH or hCG production

Luteolysis

14 +/- 2 days – life span of corpus luteum

Negative feedback of estrogen and progesterone decrease LH and FSH luteolysis decrease progesterone and estrogen secretion increasing levels of FSH and LH (late luteal phase)

Ovarian Cycle

Follicular phase – characterized by the orderly development of a single dominant follicle which matures at midcycle and prepares for ovulation Length is variable –

normally 10-14 days Dominant follicle-

secretes the greatest estradiol, increase FSH receptors in its GCs, negative feedback halts the growth of other follicles

Ovarian Cycle

Late follicular phase Estradiol levels rise

to about 200 pg/ml or higher

Small increase in progesterone

LH secretion is stimulated and in smaller amount FSH secretion

Ovarian Cycle

Ovulation LH surge initiates germinal

vesicle disruption LH stimulates synthesis of

prostaglandins and proteolytic enzymes for follicular rupture

FSH stimulates production of plasmin which aids in extrusion of the egg

Oocyte is extruded, fluid is reduced, follicular wall becomes convoluted

Ovarian Cycle Luteal phase

Granulosa cells and theca cells take up lipids and lutein – yellowish discoloration

Under LH influence, corpus luteum produces progesterone 20 ug/24 hr and some estrogen

Progesterone and estrogen exert negative feedback on FSH and LH

Ovarian Cycle

Late luteal phase Luteolysis occurs,

pregnancy does not occur

Declining levels of progesterone and estrogen levels

FSH and LH begin to rise before onset of next cycle to stimulate follicular growth

Menstrual cycle

Menarche – 13yo Menopause – 51yo Irregular during the 1st 2 years after

menarche and the 3 years before menopause

Least variable bet 20 – 40yo Mean interval is 28 +/- 7 days Polymenorrhea <21 days Oligomenorrhea >35 days Mean duration of flow is 4 =/-2

Endometrial Cycle

layers of the endometrium Decidua functionalis – zone which

proliferates and is shed during menstruation

Stratum compactum – superficial compact zone

Stratum spongiosum – deeply situated intermediate zone

Decidua basalis – deepest region, does not undergo significant proliferation, it is the source of endometrial regeneration

Endometrial Cycle Proliferative phase –

progressive growth of decidua functionalis as a response to rising estrogen Starts after menses

when endometrium is 1-2 mm and the decidua basalis is composed of primordial glands and scanty stroma

Endometrial glands initially are straight, short and narrow and will become longer and tortuous

Stroma is dense Few vascular structures

Endometrial Cycle Secretory phase – within 48-

72 hours after ovulation Progesterone-induced Day 16 –appearance of

subnuclear glycogen-containing vacuoles

Day 17 – nuclei midporion of the cells

Post ovulatory day 6 or 7 – maximal glandular activity – implantation

Post-ovulatory day 7 – edema of the stroma, spiral arterioles become longer and coiled

Day 24 – eosinophilic cuffing, leukocytic infiltration – heralds the collapse of the stroma

Endometrial Cycle

MensesAbsence of fertilizationDemise of corpus luteum –

withdrawal of ovarian steroidsSpasm of spiral arteries ischemia

and necrosisDecidua functionalis is shed

Summary

Luteal “Rescue” in the menstrual cycle

Luteolysis is prevented in the fertile cycle by the action of hCG

Continued progesterone production until placental steroidogenesis is established

Fertilization

Ovulation frees the secondary oocyte and is engulfed by the infundibulum of the fallopian tube

Sperm must be present in the fallopian tube at the time of oocyte arrival

Mature ovum becomes a zygote that undergo cleavage into blastomeres

Morula enters the uterine cavity 3 days after fertilization

Blastocyst Receptivity of endometrium is from postovulatory

production of estrogen and progesterone by the corpus luteum

Decidua

Highly modified endometrium of pregnancy and is a function of hemochorial placentation

Decidualization – transformation of secretory endometrium to decidua Dependent on estrogen and

progesterone levels and factors secreted by the implanting blastocyst during trophoblast invasion

Aging and Menopause

After menarche, as the woman ages, primary follicles in the ovary decreases (markedly reduced at 40yo)

After menopause, there may be no follicles left

1st endocrinologic sign of menopause: decreased levels of inhibin

Secondary to decreased follicle and altered granulosa cell function

FSH level

Normal adult female 5-20 IU/L, with ovulatory peak about 2

times the base level Prepubertal

Less than 5 IU/L Postmenopausal, castrate or ovarian

failure Greater than 20 IU/L