Hormon Reproduksi: Dr. Septi Handayani, M.Si
Hormon Reproduksi: Dr. Septi Handayani, M.Si
Hormon Reproduksi: Dr. Septi Handayani, M.Si
REPRODUKSI
REPRODUCTIVE
HORMONES
REPRODUCTIVE
HORMONES
Sex hormones
are synthesized from
FEMALE
REPRODUCTIVE
SYSTEM
LH
Maintains structure and secretory function of corpus
luteum
Estrogens
Have multiple functions
Progesterones
Stimulate endometrial growth and secretion
Figure 28.13
Figure 28.14a, b
THE UTERUS
Muscular organ
Mechanical protection
Nutritional support
Waste removal for the developing
embryo and fetus
THE UTERUS
Figure 28.18c
Figure 28.19b
Figure 28.20
STRUCTURAL ORGANIZATION OF
THE OVARY
The main functional unit of the
ovary is the follicle.
Follicles are composed of the
oocyte, granulosa cells, and theca
cells.
STAGES OF FOLLICULAR
GROWTH
Follicles are present in a number
of different stages of growth:
- primordial follicles (resting)
- primary, secondary, and antral
follicles
- preovulatory (Graafian) follicles
OOGENESIS
NEUROENDOCRINE REGULATION
OF OVARIAN FUNCTIONS
CNS
hypothalamus
GnRH
Pituitary
FSH
LH
E2, P
inhibin,
activin
OVARY
Follicle
Development
Ovulation
Luteinization
EFFECTS OF GNRH ON
GONADOTROPINS
GnRH is released in a pulsatile manner,
stimulating the synthesis and release of
LH and FSH.
GnRH acts through its receptor on the
pituitary gonadotroph cells, stimulating
production of phospholipase C.
Recall that IP3 pathway causes
gonadotropin release, while the DAG/PKC
pathway causes gonadotropin synthesis.
FSH
AC
ATP
Gs
cAMP
PKA
CREB
CRE
Gene Expression
Steroidogenic
enzymes
LH Receptor
Inhibin Subunits
Plasminogen
activator
androgens
aromatase
Granulosa cells
FSH
estradiol
REGULATION OF
PROGESTERONE PRODUCTION
Progesterone is produced from theca cells, mature
granulosa cells, and from the corpus luteum.
In this case, gonadotropins induce expression of
- steroidogenic acute regulatory protein
- P450 side chain cleavage
ACTIONS OF ESTRADIOL
Estradiol also has important actions in a number of
other tissues:
- causes proliferation of uterine endometrium
- increases contractility of uterine myometrium
- stimulates development of mammary glands
- stimulates follicle growth (granulosa cell
proliferation)
- effects on bone metabolism, hepatic lipoprotein
production, genitourinary tract, mood, and
cognition
Effects are mediated through the intracellular
ACTIONS OF PROGESTERONE
Progesterone exerts positive and negative feedback
effects on gonadotropin synthesis and release.
Progesterone also acts on many tissues:
- stimulates secretory activity of the uterine
endometrium
- inhibits contractility of the uterine myometrium
- stimulates mammary growth
The actions of progesterone are mediated through
an intracellular P receptor, which acts as a
transcription factor.
OVULATION
LUTEAL PHASE
ECTOPIC
IMPLANTATIONS
MALE REPRODUCTIVE
SYSTEM
Figure 28.1
1 SPERMATOCYTE
2 SPERMATOCYTE
SPERMATIDS
SPERMATIDS
2 SPERMATOCYTE
1 SPERMATOCYTE
SERTOLI CELLS:
- columnar with adjoining lateral processes
- extend from basal lamina to lumen
- Sertoli-Sertoli junctions divide seminiferous
tubules into basal and adluminal
compartments
SERTOLI
CELLS
SPERMATOGONIA
Basal Lamina
Spermatogonia (stem cells)
2n
2n
2n
mitosis
1 spermatocyte
Meiosis I completed
2 spermatocyte
n
Meiosis II
n
Early spermatids
Late spermatids
Steroid Hormones
Steroid hormones: produced in the
adrenal cortex, testis, ovary, and some
peripheral tissues (adipose tissue, the
brain!)
All steroid hormones share a typical (but
not identical) ring structure.
Steroid hormones
All steroid hormones are derived from cholesterol
and differ only in the ring structure and side
chains attached to it.
All steroid hormones are lipid soluble
Steroid hormones
Are not packaged, but synthesized and immediately
released
Are all derived from the same parent compound:
Cholesterol
Enzymes which produce steroid hormones from
cholesterol are located in mitochondria and smooth ER
Steroids are lipid soluble and thus are freely permeable to
membranes so are not stored in cells
Steroid hormones
Steroid hormones are not water soluble so have to be
carried in the blood complexed to specific binding
globulins.
Corticosteroid binding globulin carries cortisol
Sex steroid binding globulin carries testosterone and
estradiol
In some cases a steroid is secreted by one cell and is
converted to the active steroid by the target cell: an
example is androgen which secreted by the gonad and
converted into estrogen in the brain
Steroid Hormones
Steroid hormones are nonpolar (no net
charge), and can thus diffuse across lipid
membranes (such as the plasma
membrane). They leave cells shortly after
synthesis.
phospholipid
acetyl CoA
HMG-CoA
mevalonate
cholesterol
esterified cholesterol
LDL
receptor
free cholesterol
cellular synthesis
of cholesterol
free
cholesterol
level
LDL
steroid
synthesis
Steroidogenic Enzymes
Common name
"Old" name
Current name
P450SCC
3 beta-hydroxysteroid
dehydrogenase
17 alpha-hydroxylase/17,20 lyase
3 beta-HSD
P450C17
CYP17
21-hydroxylase
P450C21
CYP21A2
11 beta-hydroxylase
P450C11
CYP11B1
Aldosterone synthase
P450C11AS
CYP11B2
Aromatase
P450aro
CYP11A1
3 beta-HSD
CYP19
LH
Extracellular
lipoprotein
acetate
Cholesterol
pool
cholesterol
PKA+
ATP
cAMP
Pregnenolone
Progesterone
3HSD
P450c17
Androstenedione
TESTOSTERONE
17HSD
Functions of Hormones
Derived from Cholesterol
Product
Functions
Progesterone
Glucocorticoids (cortisol)
(produced in adrenal cortex)
(catabolic steroid)
promote gluconeogenesis;
favor breakdown of fat and
protein (fuel mobilization);
anti-inflammatory
Mineralocorticoids
(aldosterone) (produced in
adrenal glands)
Functions of Hormones
Derived from Cholesterol
Product
Functions
development of male
secondary sex
characteristics; prevents
bone resorption
Estrogen
development of female
(produced in ovaries primarily but also secondary sex
in adipose cells of males and females) characteristics; prevents
bone resorption
Vitamin D (not a steroid hormone)
(produced in the skin in response to
UV light and processed to active form
in kidney)
intestinal calcium
absorption; promotes
bone formation; prevents
phosphate loss by
kidneys
activated to
turn
Cholesterolon pathways
Progesterone
21-hydroxylase
Progesterone
Pregnenolon
e
11-Deoxycortisone
11-Deoxy21-hydroxylase cortisol
Progesterone
Aldosterone
Cortisol
Pregnenolone
DHEA
Androstenedion
Androstenedione
e
Andro
Cholesterol
Progesterone
Pregnenolone
Androstenedione
Estrone
(produced in both male
and female adipose cells)
Progesterone
Testosterone
(pathway ends
here in testes)
Estradiol
(pathway continues
to here in ovaries)
Liver
Diet
OH
25-OHase
HO
HO
25(OH) D3
Vitamin D3
UV from
sunlight
Kidney
1-OHase
Skin
OH
HO
Provitamin D3
(7-dehydrocholesterol:
Intermediate in cholesterol
synthesis)
OHase =
hydroxylase
HO
OH
Specific receptors in
intestine, bone, kidney
Ca:
Intestinal absorption
Renal reabsorption
PO4:
Intestinal absorption
Renal reabsorption
1,25(OH)2 D3
(active hormone form)
1,25-Dihydroxy Vitamin D3
1,25-dihydroxy Vitamin D3 is also derived from
cholesterol and is lipid soluble
Not really a vitamin as it can be synthesized de
novo
Acts as a true hormone
Transport of Cholesterol
Cholesterol is lipid soluble, and mostly
located associated with the external
mitochondrial membrane.
The conversion of cholesterol to steroids
occurs in the internal mitochondrial
membrane.
Now, to see if you have been paying
attention
How does cholesterol get from the external
membrane to the internal membrane?
Answer: Steroidogenic acute regulatory
protein (StAR), which transports cholesterol
into the mitochondria, moving it from the
outer membrane to the inner membrane.
Adrenal Steroids
The adrenal glands are located
immediately superior to the kidneys.
There are three classes of adrenal
steroids:
- mineralocorticoids,
- glucocorticoids, and
- androgens
Adrenal Steroidogenesis
The first enzymatic step is the conversion of
cholesterol to pregnenolone, which occurs in the
mitochondria.
This reaction is carried out by the enzyme,
cytochrome P450 side-chain cleavage (P450scc;
also called desmolase, or CYP11A1).
This is a rate limiting, nonreversible step in the
initiation of steroid biosynthesis.
This step occurs in adrenal, ovary, and testis.
Adrenal Steroidogenesis
Next, pregnenolone can be converted into
three different pathways, depending upon
whether you want to make
mineralcorticoids, glucocorticoids, or
androgens:
17-hydroxylase
pregnenolone
lyase
17-hydroxypregnenolone dehydroepiandrosterone
3-hydroxysteroid dehydrogenase
progesterone
21-hydroxylase
11-hydroxylase
18 hydroxylase/oxidase
glucocorticoids
mineralocorticoids
(aldosterone)
(cortisol)
androstenedione
Adrenal Steroidogenesis
What determines which pathway is taken?
Each step of the pathway is regulated by a specific
enzyme.
Different zones of the adrenal cortex have different
relative activities of enzymes, resulting in different
chemical reactions taking place.
These enzymes are located in the smooth ER.
In the adrenal, you do NOT have to learn the names
of these enzymes. You DO have to understand
what hormones are produced, where they are
produced, and why they are produced there.
androstenedione
testosterone
Testosterone Metabolism
Testosterone can then be converted
(mostly in peripheral tissues) to:
- DHT (dihydrotestosterone) by 5reductase, or to
-estradiol (E2) by cytochrome P450
aromatase
Important Note
Since the enzymes/pathways for producing
androgens and estrogens are utilized in
adrenal, testis, and ovary, you will be
expected to know the names of these
enzymes, and their role (example; know
that 3-HSD converts pregnenolone into
progesterone).
You are NOT responsible for drawing the
structures of these steroids. (You should
recognize the typical ring structure when
you see it, however).
Also, know that LH stimulates Leydig cell
steroidogenesis.
Ovarian Steroidogenesis
The ovary produces estrogens (primarily
estradiol), progesterone, and
androgens.
It relies largely on LDL as a source of
cholesterol for steroid synthesis
(compare with testis).
Ovarian steroids are secreted primarily
from ovarian follicles and corpora lutea.
Ovarian Follicle
LH receptor
FSH
cholesterol
estradiol
aromatase
androgens
theca cell
androgens
granulosa cell
Regulation of Ovarian
Steroidogenesis
The rate of estradiol production from follicles varies greatly
during the menstrual cycle.
Estradiol production is regulated by the effects of FSH on P450
aromatase.
Similarly, LH and FSH influence the expression of P450scc in
granulosa cells. This increases production of which gonadal
steroid?
cholesterol
P450scc
pregnenolone
3-HSD
progesterone
External stimuli
Hypothalamic
Anterior Pituitary
Adrenal cortex
Tissues
Reseptor Intraseluler
Molekul sinyal hidrofobik (hormon steroid) melalui
membran plasma terikat pada reseptor
intraseluler
Reseptor Intraseluler
Konstruksi umum nuclear receptor superfamily:
Domain pengikat ligan
Domain pengikat DNA
Daerah variabel
Reseptor Intraseluler
Setelah mengikat ligan bergerak ke inti sel
(reseptor steroid dan tiroid) dalam bentuk faktor
transkripsi mempengaruhi transkripsi gen
Reseptor Intraseluler
Mekanisme aktivasi reseptor intraseluler
Lactose biosynthesis
Importance of lactose:
1. It is less sweet than sucrose so allow the baby
to take large amount of milk without causing
nausea.
2. It is non fermentable carbohydrate so it doesn't
produce CO2 in GIT and the baby doesn't
suffer from abdominal colic or distention.
3. Lactose help growth of lactic acid producing
bacteria so help in absorption of Ca, P, Fe, Cu
which prefer acidic medium for their
absorption.
4. Lactose inhibits growth of putrefactive bacteria
which cause abdominal distention by
increasing the acidity of the intestine.
Lactose synthesis:
Lactose is synthesized in mammary gland from
D glucose and D galactose.
Galactose converted to galactose -1phosphate by galactokinase enzyme.
Galactose -1- phosphate and UDP glucose are
converted to UDP galactose and glucose -1phosphate by uridyle tranferase enzyme.
UDP galactose bounded to glucose by lactose
synthase enzyme forming lactose.
Galactosemia:
It is a condition occurs due to deficiency of galactose -1phosphate uridyle transferase.
Characterized by accumulation of galactose and galactose -1phosphate in blood.
Importance of lactose:
1. It is less sweet than sucrose so allow the baby
to take large amount of milk without causing
nausea.
2. It is non fermentable carbohydrate so it doesn't
produce CO2 in GIT and the baby doesn't
suffer from abdominal colic or distention.
3. Lactose help growth of lactic acid producing
bacteria so help in absorption of Ca, P, Fe, Cu
which prefer acidic medium for their
absorption.
N.B:
Lactose level in milk tend to vary directly with the
weight of the adult brain:
Man has the largest brain in proportion to the
body weight of all animals this may be related
to the galactolipids of the brain which contains
galactose.
N.B: