HORMON

REPRODUKSI

dr. Septi Handayani, M.Si.

REPRODUCTIVE
HORMONES

REPRODUCTIVE
HORMONES
Sex hormones
are synthesized from

cholesterol (a fatty acid) and secreted

throughout a person's lifetime at
different levels.
Male gonads (testes) produce sperm.
Female gonads (ovaries) produce egg.
Fusion of egg and sperm occur via
fertilization to produce a zygote.
The zygote undergoes division to become
an embryo, which eventually becomes a
fetus.

FEMALE
REPRODUCTIVE
SYSTEM

dr. Septi Handayani, M.Si.

HORMONES OF THE FEMALE

REPRODUCTIVE CYCLE
Control the reproductive cycle
Coordinate the ovarian and uterine
cycles

HORMONES OF THE FEMALE

REPRODUCTIVE CYCLE

Key hormones include:

FSH
Stimulates follicular development

LH
Maintains structure and secretory function of corpus
luteum

Estrogens
Have multiple functions

Progesterones
Stimulate endometrial growth and secretion

FEMALE REPRODUCTIVE ORGANS

Ovary: female gonad
Uterine Tubes (fallopian
tube, oviduct)
three parts:
infundibulum, ampulla,
isthmus

THE FEMALE REPRODUCTIVE SYSTEM IN

MIDSAGITAL VIEW

Figure 28.13

THE OVARIES AND THEIR RELATIONSHIPS TO

THE UTERINE TUBE AND UTERUS

Figure 28.14a, b

THE UTERUS

Muscular organ

Mechanical protection
Nutritional support
Waste removal for the developing
embryo and fetus

Supported by the broad ligament

and 3 pairs of suspensory ligaments

UTERINE WALL CONSISTS OF

3 LAYERS:
Myometrium outer muscular layer
Endometrium a thin, inner, glandular
mucosa
Perimetrium an incomplete serosa
continuous with the peritoneum
The site of implantation of developing embryo
And 3 parts: fundus, body, and cervix

FEMALE ACCESSORY SEX ORGANS: UTERUS

Uterine endometrium has two layers:
- basal layer
- functional layer: built up and shed each cycle

THE UTERUS

Figure 28.18c

THE UTERINE WALL

Figure 28.19b

THE UTERINE CYCLE

TO BE DISCUSSED BELOW

Figure 28.20

FUNCTIONS OF THE OVARY

Production of a mature oocyte,
capable of fertilization and
embryonic development.
Production of ovarian steroids
(estradiol, progesterone).
Production of gonadal peptides
(inhibin, activin).

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

THE CORPUS LUTEUM

After the preovulatory follicle
ovulates (releases its egg), it
forms the corpus luteum.

FEMALE REPRODUCTIVE SYSTEM

OVARY

The Ovarian Cycle

3 to 5 million OOGONIA differentiate into

PRIMARY OOCYTES during early development
OOCYTES becomes surrounded by squamous
(follicular) cells to become PRIMORDIAL FOLLICLES
most PRIMORDIAL FOLLICLES undergo
atresia leaving 400,000 at birth

oocytes at birth arrested at

Meiosis I (prophase)

FEMALE REPRODUCTIVE SYSTEM

OVARY
THREE STAGES OF OVARIAN FOLLICLES CAN
BE IDENTIFIED FOLLOWING PUBERTY:
(each follicle contains one oocyte)
(1) PRIMORDIAL FOLLICLES

OOGENESIS

- very prevalent; located in the

periphery of the cortex
- a single layer of squamous follicular
cells surround the oocyte
(2) GROWING FOLLICLES
- three recognizable stages:
(a) early primary follicle
(b) late primary follicle
(c) secondary (antral) follicle
(3) MATURE (GRAAFIAN) FOLLICLES
- follicle reaches maximum size

FEMALE REPRODUCTIVE SYSTEM

OVARIAN FOLLICLES
(1) PRIMORDIAL FOLLICLES
(2) GROWING FOLLICLES

(a) early primary follicle

- follicular cells still unilaminar but now are cuboidal in appearance
- oocyte begins to enlarge

(b) late primary follicle

- multilaminar follicular layer; cells now termed granulosa cells
- zona pellucida appears; gel-like substance rich in GAGs
- surrounding stromal cells differentiate into
theca interna and theca externa

(b) secondary (antral) follicle

- cavities appear between granulosa cells forming an antrum
- follicle continues to grow
- formation of cumulus oophorus and corona radiata
(3) MATURE (GRAAFIAN) FOLLICLES

FEMALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF
OOGENSIS AND OVULATION
HYPOTHALAMUS release of GnRF which
stimulates release of LH and FSH from the
adenohypophysis (ANTERIOR PITUITARY)

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.

Actions of FSH on Granulosa Cells

FSH

AC
ATP

Gs
cAMP
PKA
CREB

CRE

Gene Expression
Steroidogenic
enzymes
LH Receptor
Inhibin Subunits
Plasminogen
activator

Ovarian Estradiol Production

LH
Theca cells

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.

FEMALE REPRODUCTIVE SYSTEM

The Menstrual Cycle

HORMONAL REGULATION OF OOGENSIS AND OVULATION

FOLLICULAR PHASE

OVULATION

LUTEAL PHASE

10-20 primordial follicles begin to develop

in response to FSH and LH levels

theca and granulosa cells transform into the corpus

luteum and secrete large amounts of progesterone

FSH and LH stimulate theca and granulosa

production of estrogen and progesterone

if fertilization does not occur, corpus luteum

degenerates ... if fertilization does occur, HCG
released from the embryo maintains corpus luteum

surge of LH induces ovulation

FEMALE REPRODUCTIVE SYSTEM

The Menstrual Cycle
HORMONAL REGULATION OF OOGENSIS AND OVULATION
OVULATION:
sharp surge in LH
with simulataneous
increase in FSH
Meiosis I resumes;
oocyte and surrounding
cumulus break away and
are extruded
oocyte passes into
oviduct

ECTOPIC
IMPLANTATIONS

THE MENSTRUAL CYCLE

Women have ovulatory cycles of about 28 days
in length.
Day 1 of the cycle is defined as the first day of
menstruation.
There are two phases of the cycle, named after
ovarian and uterine function during that phase:
- first two weeks: follicular or proliferative stage
- second two weeks: luteal or secretory stage
The preovulatory gonadotropin surges occur in
the middle of the cycle (around day 14).

THE MENSTRUAL CYCLE: THE

OVARY
Follicular phase: small antral follicles develop, a
dominant follicle is selected and grows to the
preovulatory stage.
Midcycle: the gonadotropin surges cause ovulation of
the dominant follicle.
Luteal phase: the corpus luteum forms and becomes
functional, secreting large amounts of progesterone,
followed by estradiol (results in negative feedback,
not positive feedback, because P increases before
E2).
If pregnancy does not take place, the corpus luteum
regresses, and P and E2 levels decrease.

The Menstrual Cycle: The

Uterus
Proliferative stage: increasing estradiol levels
stimulate proliferation of the functional layer of the
uterine endometrium.
- Results in increased thickness of the endometrium.
- Increased growth of uterine glands (secrete mucus)
and uterine arteries.
Secretory stage: progesterone acts on the
endometrium.
- uterine glands become coiled and secrete more
mucus
- uterine arteries become coiled (spiral arteries)

THE MENSTRUAL CYCLE: THE

UTERUS
If pregnancy doesnt occur, P and E2 levels decrease
at the end of the secretory stage.
- vasospasm of arteries causes necrosis of tissue
- loss of functional layer with bleeding of uterine
arteries (menstruation)

FEMALE REPRODUCTIVE SYSTEM

UTERUS
ENDOMETRIUM
undergoes cyclic changes which prepare
it for implantation of a fertilized ovum
TWO LAYERS:
(1) FUNCTIONAL LAYER (stratum functionalis)
- BORDERS UTERINE LUMEN
- SLOUGHED OFF AT MENSTRATION
- CONTAINS UTERINE GLANDS

(2) BASAL LAYER (stratum basale)

- RETAINED AT MENSTRATION
- SOURCE OF CELLS FOR REGENERATION OF
FUNCTIONAL LAYER
STRAIGHT AND SPIRAL ARTERIES

FEMALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF UTERINE CYCLE
(1) PROLIFERATIVE PHASE
(2) SECRETORY PHASE
(3) MENSTRUAL PHASE

concurrent with follicular maturation and influenced by estrogens

concurrent with luteal phase and influenced by progesterone
commences as hormone production by corpus luteum declines

MALE REPRODUCTIVE
SYSTEM

dr. Septi Handayani, M.Si.

THE MALE REPRODUCTIVE SYSTEM IN MIDSAGITAL VIEW

Figure 28.1

MALE REPRODUCTIVE SYSTEM

TESTIS
TUNICA ALBUGINEA
- thick connective tissue capsule
- connective tissue septa divide
testis into 250 lobules
- each lobule contains 1-4
seminiferous tubules and
interstitial connective tissue
(1) SEMINIFEROUS TUBULES
- produce sperm
INTERSTITIAL TISSUE
- contains Leydig cells which
produce testosterone
(2) RECTUS TUBULES
(3) RETE TESTIS
(4) EFFERENT DUCTULES
(5) EPIDIDYMIS

MALE REPRODUCTIVE SYSTEM

SPERMATOGENESIS
SPERMATOGONIA

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

Daughter cell Type A

spermatogonium
remain at basal lamina
as a precursor cell

Daughter cell Type B Spermatagonium

Moves to adluminal compartment

n

1 spermatocyte

Meiosis I completed
2 spermatocyte

n
Meiosis II
n

Early spermatids
Late spermatids

MALE REPRODUCTIVE SYSTEM

SPERMATOGENESIS
THREE PHASES:
(1) Spermatogonial Phase (Mitosis)
(2) Spermatocyte Phase (Meiosis)
(3) Spermatid Phase (Spermiogenesis)
- acrosome formation; golgi granules fuse to
form acrosome that contains hydrolytic
enzymes which will enable the
spermatozoa to move through the
investing layers of the oocyte
- flagellum formation; centrioles and
associate axoneme (arrangement of
microtubules in cilia)
- changes in size and shape of nucleus;
chromatin condenses and shedding of
residual body (cytoplasm)

MALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF
MALE REPRODUCTIVE FUNCTION
HYPOTHALAMUS REGULATES ACTIVITY OF
ANTERIOR PITUITARY (ADENOHYPOPHYSIS)

ADENOHYPOPHYSIS SYNTHESIZES HORMONES

(LH and FSH) THAT MODULATE ACTIVITY OF
SERTOLI AND LEYDIG CELLS
Luteinizing Hormone (LH): stimulates testosterone
production by Leydig cells
Follicle Stimulating Hormone (FSH): stimulates production of sperm
in conjunction with testosterone by regulating activity of Sertoli cells
SERTOLI CELLS STIMULATED BY FSH AND TESTOSTERONE RELEASE
ANDROGEN BINDING PROTEIN WHICH BINDS TESTOSTERONE;
THEREBY INCREASING TESTOSTERONE CONCENTRATION WITHIN THE
SEMINIFEROUS TUBULES AND STIMULATING SPERMATOGENESIS

Synthesis of Steroid Hormones

Overview of Steroids
Peptide Hormone vs. Steroid Hormone
Synthesis
The Role of Cholesterol
Adrenal Steroids
Steroids from the Testis
Ovarian Steroids
Cortisol

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

Types of steroid hormones

Glucocorticoids; cortisol is the major
representative in most mammals
Mineralocorticoids; aldosterone being most
prominent
Androgens such as testosterone
Estrogens, including estradiol and estrone
Progestogens (also known a progestins) such as
progesterone

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

Steroids can be transformed to active steroid in

target cell

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

Polar substances are water soluble (dissolve in water),

nonpolar substances are lipid soluble.

Functions of Steroid Hormones

Steroid hormones play important roles
in:
- carbohydrate regulation
(glucocorticoids)
- mineral balance (mineralocorticoids)
- reproductive functions (gonadal
steroids)
Steroids also play roles in inflammatory
responses, stress responses, bone
metabolism, cardiovascular fitness,
behavior, cognition, and mood.

How does the synthesis of steroids

differ from that of peptide
hormones?

While peptide hormones are encoded by specific genes,

steroid hormones are synthesized from the enzymatic
modification of cholesterol.
Thus, there is no gene which encodes aldosterone, for
example.
As a result:
- There are far fewer different types of steroid hormones
than peptide hormones.
- Steroid structures are the same from species to
species
- The regulation of steroidogenesis involves control of the
enzymes which modify cholesterol into the steroid hormone
of interest.

The Role of Cholesterol in Steroid

Synthesis
The first enzymatic step in the
production of ANY steroid hormone
begins with enzymatic modification of
cholesterol

Sources of Cholesterol for Steroid

Synthesis
Cholesterol can be made within the cell from
acetyl CoA (de novo synthesis).
This is a multistep process, involving many
enzymatic reactions.
A key rate-limiting enzyme is HMG-CoA
reductase.
There is negative feedback regulation of
HMG-CoA reductase activity by cholesterol, so
that high intracellular cholesterol inhibits de
novo synthesis.HMG-CoA reductase

acetyl CoA

HMG-CoA

mevalonate

cholesterol

Sources of Cholesterol for Steroid

Synthesis
Cholesterol is also taken up by the cell in
the form of low density lipoprotein (LDL).
- LDL is a complex composed of
cholesterol, phospholipids, triglycerides,
and proteins (proteins and phospholipids
make LDL soluble in blood).
- LDL is taken into cells via LDL receptors,
and broken down into esterified
cholesterol, and then free cholesterol:
LDL

esterified cholesterol
LDL
receptor

free cholesterol

Source of Cholesterol for Steroid Synthesis

The amount of free cholesterol in the cell
is maintained relatively constant:

cellular synthesis
of cholesterol

free
cholesterol
level

esterified cholesterol level

LDL

steroid
synthesis

Cellular Localization of Cholesterol

Metabolism for Steroid Production
The first enzymatic step in steroid
synthesis is the conversion of
cholesterol into pregnenolone.
The enzyme that catalyzes this reaction
is located in the inner mitochondrial
membrane.

Steroidogenic Enzymes
Common name

"Old" name

Current name

Side-chain cleavage enzyme;

desmolase

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

Steroid hormone synthesis

All steroid hormones are derived from cholesterol.
A series of enzymatic steps in the mitochondria
and ER of steroidogenic tissues convert
cholesterol into all of the other steroid hormones
and intermediates.
The rate-limiting step in this process is the
transport of free cholesterol from the cytoplasm
into mitochondria. This step is carried out by the
Steroidogenic Acute Regulatory Protein (StAR)

Steroid hormone synthesis

The cholesterol precursor comes from cholesterol
synthesized within the cell from acetate, from
cholesterol ester stores in intracellular lipid
droplets or from uptake of cholesterol-containing
low density lipoproteins.
Lipoproteins taken up from plasma are most
important when steroidogenic cells are chronically
stimulated.

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

prepares uterus lining for

implantation of ovum

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)

maintains blood volume and

blood pressure by increasing
sodium reabsorption by kidney

Functions of Hormones
Derived from Cholesterol
Product

Functions

Androgens (strongest = testosterone)

(produced in testes primarily but weak
androgens in adrenal cortex) (anabolic
steroid)

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

General pathways for the synthesis of aldosterone and

cortisol in the adrenal cortex

Pregnenolone

DHEA

Androstenedion
Androstenedione
e
Andro

Pathway for formation of androgens in the adrenal cortex.

Beware of the hype about taking DHEA
Cortisol made in same cells as androstenedione

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)

In obese men, overproduction of estrogen in fat cells

can cause gynecomastia = excessive male breast
development
Pathways for the synthesis of testosterone (testes) and the
estrogens estradiol (ovaries) and estrone (adipose cells)

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)

Photobiosynthesis of vitamin D3 and its metabolism

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

Adrenal Cortex: Steroid Hormone Production

Aldosterone, sex hormones, cortisol

Synthesized from cholesterolsteroid ring

Adrenal Cortex: Steroid Hormone

Production

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

Organization of the Adrenal Gland

There is an adrenal cortex and adrenal medulla.
Steroids are made in three zones of the adrenal cortex:
mineralocorticoids: zona glomerulosa
glucocorticoids: zona fasciculata
androgens: zona reticularis
(Whats made in the adrenal medulla??)

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.

Production of Steroids in the Testis

The main steroid produced in the male
is testosterone, from the testis. In
addition, the testis makes some
androstenedione, dihydrotestosterone,
and estradiol.
In the male, there is peripheral
conversion of testosterone to
dihydrotestosterone (in androgen
target tissues, like muscle) and
estradiol (mostly in adipose tissue).

Organization of the Testis

The testis is organized into two main
parts:
- seminiferous tubules: production of
sperm cells, location of Sertoli cells (stay
tuned...)
- interstitial tissue: outside of the
seminiferous tubules; the steroidogenic
cell is the Leydig cell

Function of Leydig Cells

Leydig cells: respond to luteinizing
hormone (LH) with steroid production
(primarily testosterone).
Leydig cells are unusual in that they rely
on de novo synthesis of cholesterol
more than other cells (50%). Thus, only
about 50% of cholesterol used in steroid
production is obtained from LDL.

Pathway of Testosterone Production

in the Testis
The production of androgens from
cholesterol is identical to that in the
adrenal, except that it continues from
androstenedione to testosterone.
17-hydroxysteroid
oxidoreductase

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

The follicle is the basic functional unit of the ovary.

It is composed of an oocyte, granulosa cells, and
theca cells.

When the follicle ruptures, it becomes a corpus luteum.

The Puzzle of Estrogen Production

in the Ovary
In the ovary, estradiol is formed from the
conversion of testosterone into estradiol by
the enzyme cytochrome P450 aromatase.
This occurs in granulosa cells.
However, granulosa cells do not have the
enzyme 17-hydroxylase/lyase, and thus
cannot convert progesterone into
androgens.
Where do the androgens required for
estrogen production in granulosa cells
come from?

The Two-Cell Theory of Estrogen

Production in the Ovary
Numerous studies have now shown that
the androgens required for aromatization
come from the neighboring theca cells:
LH

LH receptor

FSH

cholesterol
estradiol
aromatase
androgens

theca cell

androgens

granulosa cell

Other Steroid Production in the

Ovary
After ovulation, the corpus luteum produces progesterone and
estradiol, to support the uterine endometrium during
pregnancy.
Progesterone is also produced from theca cells and granulosa
cells.

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

Cortisol Effects: Body Responses to Stress

Permissive effect on glucagon

Memory, learning and mood
Gluconeogenesis
Skeletal muscle breakdown
Lipolysis, calcium balance
Immune depression
Circadian rhythms

Cortisol Effects: Body Responses to Stress

Figure 23-4: Circadian rhythm of cortisol secretion

Control of Cortisol Secretion: Feedback

Loops

External stimuli
Hypothalamic
Anterior Pituitary
Adrenal cortex
Tissues

Figure 23-3: The control pathway for cortisol

Cortisol: Role in Diseases and

Medication
Use as immunosuppressant
Hyperimmune reactions (bee stings)
Serious side effects

Hypercortisolism (Cushing's syndrome)

Tumors (pituitary or adrenal)
Iatrogenic (physician caused)

Hypocortisolism (Addison's disease)

Steroid Hormones: Characteristics

Are made from cholesterol, are lipophilic &

can enter target cell
Are immediately released from cell after
synthesis
Interact with cytoplasmic or nuclear receptors
Activate DNA for protein synthesis
Are slower acting and have longer half-life
than peptide hormones
Examples: cortisol, estrogen & testosterone

Steroid Hormones: Review the

Structure

Steroid Hormones: Molecular

Action

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

Proses Sinyal Melalui Reseptor Intraseluler

Ligan untuk reseptor intra sel: hormon lipofilik
dapat masuk sel melalui proses difusi berikatan
dengan reseptor nuklear
Reseptor nuklear juga disebut reseptor yang dapat
larut
Reseptor nuklear merupakan suatu protein pengikat
DNA spesifik yang berikatan dengan sekuens DNA
tertentu yang disebut Hormone Responsive Element
(HRE)

Proses Sinyal Melalui Reseptor Intraseluler

Interaksi antara reseptor yang telah mengikat
hormon dengan HRE akan merangsang ekspresi
gen

Proses Sinyal Melalui Reseptor Intraseluler

Proses sinyal relatif sederhana, ditujukan untuk
suatu perubahan jangka lama banyak
ditemukan pada proses perkembangan dan
diferensiasi organ
Aktivasi transkripsi pada proses sinyal ini dapat
terjadi melalui 2 jalur:
Interaksi domain transaktivasi dengan
komponen dari kompleks inisiasi transkripsi
Chromatin remodeling

Caraka Kedua (Second Messenger)

Merupakan molekul kecil yang terdapat intra sel,
dan dapat mentransmisikan dan
mengamplifikasikan molekul sinyal awal
Contoh: cAMP, cGMP, inositol trifosfat (IP3), diasil
gliserol (DAG), ion kalsium

Caraka Kedua (Second Messenger)

Caraka Kedua (Second Messenger)

Pemecahan phosphatidylinositol biphosphanate (PIP2) oleh fosfolipase C (PLC)
menjadi 2 caraka kedua : IP3 dan DAG

Lactose biosynthesis

 Lactose (milk sugar) is the only carbohydrate

of milk.
It is a reducing disaccharide consists of
glucose and galactose.
Human's milk contains 7% lactose while cow's
milk contains 5% lactose.
Lactose may be excreted in urine during last
third of pregnancy physiologically so it should
be differentiated from glucose by osazon test.

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.

Lactose synthase enzyme:

Consists of two subunits:
1. Catalytic subunit:
Can't synthesize lactose.
It catalyze the attachment of galactose to protein to
form glycoprotein.
2. Modifier subunit:
Alter the specificity of the catalytic subunite which
make galactose bounded to glucose to form lactose.
. During pregnancy little modifier subunite is formed in
the mammary gland so no lactose synthesized But at
birth large amount of modifier is formed helping the
synthesis of lactose in mammary gland.

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
disturbance by increasing the acidity of
the intestine.
5. On hydrolysis it produce glucose and
galactose:
Glucose act as source of energy.
Galactose used for synthesis of
galactolipids so help in development of
nerve tissues.

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.

6. Lactose has a laxative effect as some of

glucose is fermented by the intestinal
bacteria producing CO2 which stimulate
the intestinal movement.

N.B:

If the milk is taken by the adult in large

amount result in diarrhea due to decrease

in lactase enzyme so lactose is hydrolyzed
by intestinal bacteria to glucose and
galactose.
Glucose is fermented producing CO2 and
abdominal distention.
Non
fermentable
galactose
and
unhydrolyzed lactose increase osmotic
pressure of the intestine leads to diarrhea.