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
The Ovarian Cycle
OVARY
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

- very prevalent; located in the
periphery of the cortex
- a single layer of squamous follicular
cells surround the oocyte
OOGENESIS

(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

LH FSH Follicle
Development
E2, P
Ovulation
inhibin, OVARY
Luteinization
activin
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
Gene Expression
cAMP
Steroidogenic
enzymes
PKA LH Receptor
Inhibin Subunits
Plasminogen
CREB activator
CRE
 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 estrogen receptors
(alpha and beta), and possible membrane effects.
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
OVULATION
FOLLICULAR PHASE
10-20 primordial follicles begin to develop
in response to FSH and LH levels
FSH and LH stimulate theca and granulosa
production of estrogen and progesterone
surge of LH induces ovulation
LUTEAL PHASE
theca and granulosa cells transform into the corpus
luteum and secrete large amounts of progesterone
if fertilization does not occur, corpus luteum
degenerates ... if fertilization does occur, HCG
released from the embryo maintains corpus luteum
 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 concurrent with follicular maturation and influenced by estrogens
(2) SECRETORY PHASE concurrent with luteal phase and influenced by progesterone
(3) MENSTRUAL PHASE 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 SPERMATOGONIA
CELLS
 Basal Lamina
Daughter cell Type A
spermatogonium
2n 2n
Spermatogonia (stem cells) remain at basal lamina
as a precursor cell

mitosis 2n Daughter cell Type B Spermatagonium

Moves to adluminal compartment

n
1 spermatocyte
Meiosis I completed

n 2 spermatocyte
n
Meiosis II

n n n n Early spermatids

n n n n 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 free cholesterol

LDL
receptor
 Source of Cholesterol for Steroid Synthesis
The amount of free cholesterol in the cell is
maintained relatively constant:

cellular synthesis
of cholesterol free
cholesterol steroid
level synthesis

esterified cholesterol level

LDL
 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; P450SCC CYP11A1

desmolase

3 beta-hydroxysteroid 3 beta-HSD 3 beta-HSD

dehydrogenase
17 alpha-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11 beta-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro 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.
 Extracellular
lipoprotein LH
Cholesterol
acetate pool
ATP

cholesterol cAMP
PKA+

Pregnenolone
3HSD
Progesterone
P450c17
Androstenedione
17HSD
TESTOSTERONE
 Functions of Hormones
Derived from Cholesterol

Product
Progesterone
Glucocorticoids (cortisol)
(produced in adrenal cortex)
(catabolic steroid)
Mineralocorticoids
(aldosterone) (produced in
adrenal glands)
Functions
prepares uterus lining for
implantation of ovum
promote gluconeogenesis;
favor breakdown of fat and
protein (fuel mobilization);
anti-inflammatory
maintains blood volume and
blood pressure by increasing
sodium reabsorption by kidney
 Functions of Hormones
Derived from Cholesterol

Product Functions
Androgens (strongest = testosterone) development of male
(produced in testes primarily but weak secondary sex
androgens in adrenal cortex) (anabolic characteristics; prevents
steroid) 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) intestinal calcium
(produced in the skin in response to absorption; promotes
UV light and processed to active form bone formation; prevents
in kidney) phosphate loss by
kidneys
 activated to
turn
Cholesterolon pathways Pregnenolon Progesterone
e

Progesterone 11-Deoxy- Aldosterone

cortisone
21-hydroxylase

Progesterone 11-Deoxy- Cortisol

21-hydroxylase 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 Pregnenolone Progesterone

Progesterone Androstenedione Testosterone

(pathway ends
here in testes)

Estrone
(produced in both male
and female adipose cells) 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 OHase =
Diet OH
hydroxylase
25-OHase

HO
HO
Vitamin D3 25(OH) D3
Kidney Specific receptors in
UV from 1-OHase intestine, bone, kidney
Skin
sunlight
Ca:
OH Intestinal absorption
Renal reabsorption

HO 7 PO4:
Intestinal absorption
Provitamin D3 HO OH Renal reabsorption
(7-dehydrocholesterol: 1,25(OH)2 D3
Intermediate in cholesterol (active hormone form)
synthesis)

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 lyase
pregnenolone 17-hydroxypregnenolone dehydroepiandrosterone
3-hydroxysteroid dehydrogenase
progesterone androstenedione
21-hydroxylase

11-hydroxylase

18 hydroxylase/oxidase glucocorticoids
mineralocorticoids (cortisol)
(aldosterone)
 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 5-reductase, 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 FSH
LH receptor

cholesterol

estradiol

aromatase
androgens androgens

theca cell 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?

P450scc 3-HSD
cholesterol pregnenolone 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 -1-
phosphate by galactokinase enzyme.
Galactose -1- phosphate and UDP glucose are
converted to UDP galactose and glucose -1-
phosphate 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 -1-
phosphate uridyle transferase.
Characterized by accumulation of galactose and galactose -1-
phosphate 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.