ENDOCRINOLOGY OF

THE REPRODUCTIVE SYSTEM

M. Djauhari Widjajakusumah

THE FEMALE
REPRODUCTIVE SYSTEM

Ovarian
Ovarian Cycle
Cycle
Follicle
Follicle Development
Development -- Follicular
Follicular Phase
Phase
Primordial follicle

formed during fetal life (3rd - 7th month)

contains a primary oocyte surrounded by a single layer of granulosa
cells
more than 2000.000 in each ovary at birth

Primary follicle

consists of a primary oocyte surounded by multiple layers of granulosa

cells and a layer of theca cells
developed from several primordial follicles each month starting at
puberty (10-14 yrs)

Ovarian
Ovarian Cycle
Cycle
Follicle
Follicle Development
Development -- Follicular
Follicular Phase
Phase

Secondary follicle

developed from primary follicles at the beginning of each

cycle
in response to the rising levels of FSH
granulosa cells continue to proliferate, secrete a fluid,
forming a fluid-filled cavity: antrum

Ovarian
Ovarian Cycle
Cycle
Follicle
Follicle Development
Development -- Follicular
Follicular Phase
Phase
Vesicular / Graafian / Mature follicle

only one secondary follicle (dominant follicle) completely

matures Graafian follicle; other secondary follicles
disintegrate / atresia (atretic follicles)

Graafian follicle ruptures ovulation (at about the 14th

day of the cycle) secondary oocyte ejected into the
open end of Fallopian tube

Follicular
Follicular Atresia
Atresia

In mammals, 99.9% of all the follicles (oocytes) die by atresia.

Only + 400 reach ovulatory stage

A fundamental property of atresia is the activation of apoptosis

in the oocyte and granulosa cells. Apoptosis is a complex
process involving ligand signaling pathways that are coupled to
cell death.

The importance of FSH in preventing apoptosis has led to the

concept that FSH is a follicle survival factor

The physiological mechanisms governing atresia remain poorly

understood.

THE MENSTRUAL CYCLE

Regular cyclic changes of the reproductive system of

women

Regarded as periodic preparation for fertilization and

pregnancy

Periodic vaginal bleeding that occurs with the shedding of

the uterine mucosa (menstruation)

Length of the cycle is variable; average figure is 28 days

Ovarian cycle and uterine cycle

Parturition
Parturition

Estrogens increase the number of oxytocin receptors in

myometrium > 100 x during pregnancy

Reaches its peak during early labor

Uterine distention late in pregnancy may also increase the
number of oxytocin receptors

Increased number of oxytocin receptors causes uterus to

respond to normal plasma oxytocin concentration in the
early labor stage

Parturition
Parturition
Estrogens Increased oxytocin receptors Uterine distention
Prostaglandin
Uterine contractions
Dilatation of cervix and distention of vagina
Stimuli from cervix and vagina
Increased secretion of oxytocin

Parturition
Parturition

Oxytocin increases unterine contractins in two ways:

1. Acts directly on myometrium, uterine smooth muscles
contract
2. Stimulates prostaglandins formation in the decidua.
Prostaglandins enhance the oxytocin-induced contractions
Spinal reflexes and voluntary contractions of abdominal
muscles also aid in delivery

MENOPAUSE
 Menopause is the time in a woman's life when the function of the
ovaries ceases.
 Menopause is defined as absence of menstrual periods for 12
months.
 The menopausal transition starts with varying menstrual cycle length
and ends with the final menstrual period.
 Perimenopause means "around the time of menopause.
 Postmenopause is the entire period of time that comes after the last
menstrual period.

MENOPAUSE
 Between the ages of 45 - 55 year
 may occur as earlier as the 30s or 40s or may not occur until a
woman reaches her 60s.
 Unresponsiveness of human ovaries to gonadotropin with advancing
age
 Declining function of the ovaries --> sexual cycles disappear
(menopause)
 Declining number of primordial follicle
 No appreciable quantities of ovarian progesterone and estradiol
 Atrophic uterus and vagina
 Increased FSH and LH

THE PERIMENOPAUSAL AND MENSTRUAL CYCLICITY

PERIMENOPAUSE
Follicle pool
inhibin
FSH

Acceleration of Follicular
Maturation
Shorter Cycle

Follicle Pool
Estradiol

Delayed (+) feedback

Longer Cycle

MENOPAUSE
Follicle Pool
Estradiol

LH

FSH

Cycle Arrest

MENOPAUSE

Common
Common Symptoms
Symptoms
Hot
Hot flashes
flashes // hot
hot flushes
flushes (75%):
(75%): warmth
warmth sensation
sensation spreading
spreading
from
from trunk
trunk to
to face
face

prevented
prevented by
by estrogen
estrogen treatment
treatment

unknown
unknown cause
cause

coincide
coincide with
with surges
surges of
of LH
LH secretion
secretion (bursts
(bursts at
at intervals
intervals of
of
30
30 -- 60)
60)

LH
LH is
is not
not responsible
responsible for
for the
the symptom
symptom

Night
Night sweats
sweats

Various
Various psychic
psychic symptoms
symptoms

MENOPAUSE
Hot
Hot flashes
flashes &
& night
night sweats
sweats
A
A feeling
feeling of
of warmth
warmth that
that spreads
spreads over
over the
the body
body and
and is
is often
often most
most
pronounced
pronounced in
in the
the head
head and
and chest.
chest.
Usually
Usually last
last from
from 30
30 seconds
seconds to
to several
several minutes
minutes
Sometimes
Sometimes associated
associated with
with flushing
flushing and
and is
is sometimes
sometimes followed
followed by
by
perspiration.
perspiration.
Are
Are likely
likely due
due to
to aa combination
combination of
of hormonal
hormonal and
and biochemical
biochemical
fluctuations
fluctuations brought
brought on
on by
by declining
declining estrogen
estrogen levels.
levels.
May
May begin
begin before
before the
the menstrual
menstrual irregularities
irregularities characteristic
characteristic of
of
menopause
menopause begin.
begin.
About
About 80%
80% of
of women
women will
will be
be finished
finished having
having hot
hot flashes
flashes after
after five
five
years
years (in
(in about
about 10%
10% of
of women,
women, hot
hot flashes
flashes can
can last
last as
as long
long as
as 10
10
years)
years)
Tend
Tend to
to decrease
decrease in
in frequency
frequency over
over time.
time.
Sometimes
Sometimes hot
hot flashes
flashes are
are accompanied
accompanied by
by night
night sweats,
sweats,
resulting
resulting in
in unrefreshing
unrefreshing sleep
sleep and
and daytime
daytime tiredness
tiredness

MENOPAUSE
Vaginal
Vaginal symptoms
symptoms
A
A result
result of
of the
the lining
lining tissues
tissues of
of the
the vagina
vagina becoming
becoming thinner,
thinner, dryer,
dryer,
and
and less
less elastic
elastic as
as estrogen
estrogen levels
levels fall.
fall.
Symptoms
Symptoms may
may include
include vaginal
vaginal dryness,
dryness, itching,
itching, or
or irritation
irritation
and/or
and/or pain
pain with
with sexual
sexual intercourse
intercourse (dyspareunia).
(dyspareunia).
The
The vaginal
vaginal changes
changes also
also lead
lead to
to an
an increased
increased risk
risk of
of vaginal
vaginal
infections.
infections.

MENOPAUSE
Urinary
Urinary symptoms
symptoms
The
The lining
lining of
of the
the urethra
urethra undergoes
undergoes changes
changes similar
similar to
to the
the tissues
tissues
of
of the
the vagina,
vagina, becomes
becomes dryer,
dryer, thinner,
thinner, and
and less
less elastic
elastic with
with
declining
declining estrogen
estrogen levels.
levels.
Can
Can lead
lead to
to an
an increased
increased risk
risk of
of urinary
urinary tract
tract infection,
infection, feeling
feeling the
the
need
need to
to urinate
urinate more
more frequently,
frequently, or
or leakage
leakage of
of urine
urine (urinari
(urinari
incontinence).
incontinence).
The
The incontinence
incontinence can
can result
result from
from aa strong,
strong, sudden
sudden urge
urge to
to urinate
urinate
or
or may
may occur
occur during
during straining
straining when
when coughing,
coughing, laughing,
laughing, or
or lifting
lifting
heavy
heavy objects.
objects.

MENOPAUSE
Emotional
Emotional and
and cognitive
cognitive symptoms
symptoms
Women
Women in
in perimenopause
perimenopause often
often report
report aa variety
variety of
of cognitive
cognitive
(thinking)
(thinking) and/or
and/or emotional
emotional symptoms:
symptoms:
fatigue,
fatigue, memory
memory problems,
problems, irritability,
irritability, rapid
rapid changes
changes in
in mood
mood
Difficult
Difficult to
to determine
determine which
which behavioral
behavioral symptoms
symptoms are
are due
due directly
directly
to
to the
the hormonal
hormonal changes
changes of
of menopause
menopause
Night
Night sweats
sweats that
that can
can also
also contribute
contribute to
to feelings
feelings of
of tiredness
tiredness and
and
fatigue,
fatigue, which
which can
can have
have an
an effect
effect on
on mood
mood and
and cognitive
cognitive
performance
performance
Many
Many women
women may
may be
be experiencing
experiencing other
other life
life changes
changes during
during the
the
time
time of
of perimenopause
perimenopause or
or after
after menopause,
menopause, such
such as
as stressful
stressful life
life
events,
events, that
that may
may also
also cause
cause emotional
emotional symptoms.
symptoms.

MENOPAUSE
Osteoporosis
Osteoporosis
Osteoporosis
Osteoporosis is
is the
the deterioration
deterioration of
of the
the quantity
quantity and
and quality
quality of
of
bone
bone that
that causes
causes an
an increased
increased risk
risk of
of fracture.
fracture.
The
The density
density of
of the
the bone
bone (bone
(bone mineral
mineral density)
density) normally
normally begins
begins to
to
decrease
decrease in
in women
women during
during the
the fourth
fourth decade
decade of
of life.
life.
Normal
Normal decline
decline in
in bone
bone density
density is
is accelerated
accelerated during
during the
the
menopausal
menopausal transition.
transition.
Age
Age and
and the
the hormonal
hormonal changes
changes due
due to
to the
the menopause
menopause transition
transition
act
act together
together to
to cause
cause osteoporosis.
osteoporosis.
The
The process
process leading
leading to
to osteoporosis
osteoporosis can
can operate
operate silently
silently for
for
decades.
decades. Women
Women may
may not
not be
be aware
aware of
of their
their osteoporosis
osteoporosis until
until
suffering
suffering aa painful
painful fracture.
fracture.

OSTEOBLASTOGENESIS - OSTEOCLASTOGENESIS
Bone Marrow Culture
Fibroblast ColonyForming Unit
(Osteoprogenitor cells)
Osteoblast, Fibroblast
Chondrocytes, Adipocytes
Progenitors
PTH
Calcitriol
Osteoblastic
precursor cells

(+)
(+)
Osteoblast
IGF-1
Bone Forming

Granulocyte-Macrophag
Colony Forming Unit
(Hematopoetic cells)
Osteoclast, Monocytes
Macrophage Progenitors

(-)

RANK-L

Estrogen
Androgen

Early pre-osteoclast
(+)
Late pre-osteoclast
(+)
Osteoclast
Bone Resorption

(RANK: receptor activator of nuclear factor kappa B) =

(ODF: osteoclast differentiation factor)

Osteoblast
Osteoblast Osteoclast
Osteoclast Communication
Communication
osteoblast
osteoblast (&
(& osteoblast
osteoblast precursors)
precursors)
estrogens
estrogens ++

--

glucocorticoids
glucocorticoids
PTH
PTH
osteoprotegerin
osteoprotegerin (OPG)
(OPG)
free-floating
free-floating decoy
decoy receptor
receptor

osteoclast
osteoclast precursors
precursors
RANK
RANK receptor
receptor
++

++ --

estrogens
estrogens

OPG-ligand
OPG-ligand
(RANK
(RANK ligand)
ligand)

osteoclast
osteoclast ++
RANK
RANK receptor
receptor
osteoclast
osteoclast activity
activity

RANK
RANK ligand
ligand
(osteoblast)
(osteoblast) ++

bone
bone resorption
resorption
PTH,
PTH, DHC
(vit D
D33),
), IL
IL 11- 44 -- 6-11-17,
DHC (vit
6-11-17, TNF-alfa
TNF-alfa

MENOPAUSE
Cardiovascular
Cardiovascular disease
disease
Prior
Prior to
to menopause,
menopause, women
women have
have aa decreased
decreased risk
risk of
of heart
heart
disease
disease and
and stroke
stroke when
when compared
compared with
with men.
men. Around
Around the
the time
time of
of
menopause,
menopause, womens
womens risk
risk of
of cardiovascular
cardiovascular disease
disease increases.
increases.
Coronary
Coronary heart
heart disease
disease rates
rates in
in postmenopausal
postmenopausal women
women are
are two
two
to
to three
three times
times higher
higher than
than in
in women
women of
of the
the same
same age
age who
who have
have
not
not reached
reached menopause.
menopause.
The
The increased
increased risk
risk for
for cardiovascular
cardiovascular disease
disease may
may be
be related
related to
to
declining
declining estrogen
estrogen levels,
levels, but
but postmenopausal
postmenopausal women
women are
are not
not
advised
advised to
to take
take hormone
hormone therapy
therapy simply
simply as
as aa preventive
preventive measure
measure
to
to decrease
decrease their
their risk
risk of
of heart
heart attack
attack or
or stroke.
stroke.

MENOPAUSE
Hormone
Hormone therapy
therapy
Estrogen
Estrogen and
and progesterone
progesterone therapy
therapy
Oral
Oral contraceptive
contraceptive pills
pills
Plant
Plant estrogens
estrogens (phytoestrogens,
(phytoestrogens, isoflavones)
isoflavones)
Local
Local (vaginal)
(vaginal) hormone
hormone treatments
treatments

Antidepressant
Antidepressant medications
medications
Lifestyle
Lifestyle factors
factors in
in controlling
controlling the
the symptoms
symptoms and
and
complications
complications of
of menopause
menopause

MENOPAUSE
Hormone
Hormone therapy
therapy
Estrogen
Estrogen and
and progesterone
progesterone therapy
therapy

Hormone
Hormone replacement
replacement therapy
therapy (HRT),
(HRT), consists
consists of
of estrogens
estrogens or
or aa
combination
combination of
estrogens and
and progesterone
progesterone (progestin).
(progestin).
of estrogens
The
The most
most effective
effective way
to control
control the
related to
to
way to
the symptoms
symptoms of
of menopause
menopause related
declining
declining estrogen
estrogen levels
levels such
flashes and
such as
as hot
hot flashes
and vaginal
vaginal dryness.
dryness.
Combination
Combination of
of estrogens
estrogens and
and progesterone
progesterone increases
increases risk
risk for
for stroke
stroke
and
and breast
breast cancer.
cancer.
Estrogen
Estrogen therapy
therapy alone
is associated
increased risk
risk for
for stroke,
stroke,
alone is
associated with
with an
an increased
and
and endometrial
endometrial cancer,
cancer, but
but not
not for
for breast
breast cancer.
cancer.
Must
Must take
take into
into account
account the
inherent risks
risks and
of the
treatment
the inherent
and benefits
benefits of
the treatment
along
along with
woman's own
own medical
medical history.
history.
with each
each woman's
ItIt is
is currently
currently recommended
recommended that
that hormone
hormone therapy
therapy should
should be
be used
used at
at the
the
smallest
smallest effective
effective dose
dose for
for the
the shortest
shortest possible
possible time.
time.

MENOPAUSE
Hormone
Hormone therapy
therapy
Oral
Oral contraceptive
contraceptive pills
pills
Another
Another form
form of
of hormone
hormone therapy
therapy often
often prescribed
prescribed for
for women
women
in
in perimenopause
perimenopause to
to treat
treat irregular
irregular vaginal
vaginal bleeding.
bleeding.
Prior
Prior to
to treatment,
treatment, other
other causes
causes of
of erratic
erratic vaginal
vaginal bleeding
bleeding
must
must be
be excluded.
excluded.
Women
Women in
in the
the menopausal
menopausal transition
transition tend
tend to
to have
have considerable
considerable
breakthrough
breakthrough bleeding
bleeding when
when given
given estrogen
estrogen therapy.
therapy.
Oral
Oral contraceptives
contraceptives are
are often
often given
given to
to women
women in
in menopause
menopause
transition
transition to
to regulate
regulate menstrual
menstrual periods,
periods, relieve
relieve hot
hot flashes,
flashes, as
as
well
well as
as to
to provide
provide contraception.
contraception.

MENOPAUSE
Hormone
Hormone therapy
therapy
Plant
Plant estrogens
estrogens (phytoestrogens,
(phytoestrogens, isoflavones)
isoflavones)
Chemical compounds
compounds found
found in
in soy
soy and
and other
other plants
plants that
that are
are
Chemical
phytoestrogens,
phytoestrogens, or
or plant-derived
plant-derived estrogens.
estrogens.

Have aa chemical
chemical structure
structure that
to the
the estrogens
estrogens naturally
naturally
Have
that is
is similar
similar to
produced
produced by
by the
the body
body

Effectiveness as
as an
an estrogen
estrogen has
has been
been estimated
estimated to
to be
be much
much lower
lower
Effectiveness
than
than true
true estrogens,
estrogens, has
has been
been estimated
estimated to
to be
be only
only 1/1000
1/1000 to
to
1/100,000
1/100,000 of
of that
that of
of estradiol.
estradiol.

May help
help relieve
relieve hot
hot flashes
flashes and
and other
other symptoms
symptoms of
of menopause.
menopause.
May
Further research
research is
is needed
needed to
to fully
fully characterize
characterize the
the safety
safety and
and
Further
potential
potential risks
risks of
phytoestrogens.
of phytoestrogens.

MENOPAUSE
Hormone
Hormone therapy
therapy
Local
Local (vaginal)
(vaginal) hormone
hormone treatments
treatments

Vaginal
Vaginal hormonal
hormonal treatments
treatments for
for the
the symptoms
symptoms of
of vaginal
vaginal
estrogen
estrogen deficiency.
deficiency.

Include
Include the
the vaginal
vaginal estrogen
estrogen ring,
ring, vaginal
vaginal estrogen
estrogen cream,
cream, or
or
vaginal
vaginal estrogen
estrogen tablets.
tablets.

Local
Local and
and oral
oral estrogen
estrogen treatments
treatments are
are sometimes
sometimes combined.
combined.

MENOPAUSE
Antidepressant
Antidepressant medications
medications
Effective
Effective in
in controlling
controlling the
the symptoms
symptoms of
of hot
hot flashes
flashes in
in up
up to
to 60%
60% of
of
women.
women.
May
May be
be associated
associated with
with side
side effects,
effects, including
including decreased
decreased libido
libido or
or
sexual
sexual dysfunction.
dysfunction.

MENOPAUSE
Lifestyle
Lifestyle factors
factors in
in controlling
controlling the
the symptoms
symptoms and
and
complications
complications of
of menopause
menopause
Many
Many of
of the
the symptoms
symptoms of
of menopause
menopause and
and the
the medical
medical
complications
complications that
that may
may develop
develop in
in postmenopausal
postmenopausal women
women can
can
be
be lessened
lessened or
or even
even avoided
avoided by
by taking
taking steps
steps to
to lead
lead aa healthy
healthy
lifestyle.
lifestyle.
Regular
Regular exercise
exercise can
can help
help protect
protect against
against cardiovascular
cardiovascular disease
disease
as
as well
well as
as osteoporosis,
osteoporosis, and
and exercise
exercise also
also has
has known
known mental
mental
health
health benefits.
benefits.
Proper
Proper nutrition
nutrition and
and smoking
smoking cessation
cessation will
will also
also reduce
reduce your
your risk
risk
of
of cardiovascular
cardiovascular disease.
disease.

Mammary Gland and

Lactation

Development
Development of
of The
The Breasts
Breasts

Estrogens are primarily responsible for proliferation of mammary ducts

Prolactin in humans may also be needed for mammary glands

development at puberty

Increased prolactin levels, and high levels of estrogens and

progesterone (and possibly hCG) cause full breast lobulo-alveolar
development during pregnancy

Cortisol, insulin, and growth hormone are necessary for mammary

development

Progesterone are primarily responsible for the development of the

lobules

Lactation
Lactation Secretion
Secretion and
and Ejection
Ejection of
of Milk
Milk

Prolactin causes formation and secretion of milk in estrogen- and

progesterone-primed breasts

Oxytocin causes contraction of myoepithelial cells, leads to milk

ejection through the nipple

Estrogens increase the number of oxytocin receptors on myoepithelial

cells

Estrogens (and possibly also progesterone) antagonize the milk

production effect of prolactin

After parturition, abrupt decline of estrogens and progesterone initiates

lactation in humans takes 1-3 days for the milk to come in

Prolactin
Prolactin Synthesis
Synthesis and
and Control
Control

Produced by the lactotrophs cells of the anterior pituitary gland

During lactation, suckling of the breast results in an increased release of

prolactin ( decreased PIH, increased PRH)

Response to suckling declines with time post-partum, may well remain

above normal for 18 months or more if suckling frequency is maintained
at a high level basal levels

Under stimulatory control of thyroid releasing hormone (TRH)

Increased release at night
In females - increased release during puberty
Prolactin levels are high during pregnancy - oestrogen causes an
increase in numbers of lactotrophs

Prolactin Levels

High during pregnancy, drifts down to its normal level after the baby is
born

By the end of the first week after birth, prolactin is down to 50 percent of
its normal level, after three or four months, it is the same as it was before
pregnancy

Every time the baby suckles, there is a new burst of prolactin telling the
body to make milk and a burst of oxytocin telling it to eject the milk

The more the mother nurses the baby, the more milk the body will
produce; suckling is simply the message to the body to make more of it.

Contraceptive effect of high levels of prolactin

In non breast-feeding women

FSH levels quickly return to normal menstrual cycle levels within a week
or two post-partum; having the 1st menstrual period + 6 weeks after
delivery

In breast-feeding women
During lactational amenorrhoea (25-30 weeks) FSH levels appear to be
inadequate for ovarian function
LH levels are very low immediately postpartum, by 15 to 20 days
increase significantly and remain throughout lactation on the lower side
of normal
Prolactin inhibits normal pulsatile secretion of GnRH, inhibits GnRH
action on pituitary, antagonize gonadotropin action on ovaries, no
midcycle LH surge anovulation
Prolactin inhibits the ovary estrogen deficient

Newborn Baby Body-weight Loss

Newborns are nourished from their mother's milk or from a

bottle because they can only swallow liquids.

Since newborns can only digest about 30 milliliters of mother's

milk or formula at a time, they must be fed often, usually about
every 4 hours.

They can lose as much as 10% of their body weights in the first
few days after birth because they need more food than they can
consume. At about the tenth day of life, the newborn regains
the lost weight and starts to gain about 28 grams per day.

Thank
you