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

GnRH

pituitary

FSH, LH
ovary

uterus
Estrogen
Progesterone

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

Neuroanatomy
Hypothalamus
GnRH production
anterior
hypothalamus
medial basal
hypothalamus
arcuate nucleus
Pituitary
Neurohypophysis
median eminence
infundibular stalk
posterior lobe
Adenohypophysis
anterior 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 cycle
follicular 1 pulse/hr
luteal 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

GnRH

Anovulation and
amenorrhea
GnRH secretion
is regulated by
ovarian steroids
and the
pituitary
gonadotrophins

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 2436 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 thecainterstitial 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 folliclesecretes 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 12 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 4872 hours after ovulation

Progesterone-induced
Day 16 appearance of
subnuclear glycogencontaining 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

Menses
Absence of fertilization
Demise of corpus luteum
withdrawal of ovarian steroids
Spasm of spiral arteries ischemia
and necrosis
Decidua 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