Major hormones and systems types and metabolism of testosteron

1. Metabolism of Androgens
Samova Sanman
M.Sc Human Genetics
School of science

2. Major hormones and systems
 Hypothalamus produces releasing factors that
stimulate production of anterior pituitary
hormone which act on peripheral endocrine
gland to stimulate release of third hormone
 Posterior pituitary hormones are synthesized in
neuronal cell bodies in the hypothalamus and
are released via synapses in posterior pituitary.
 Oxytocin and antidiuretic hormone (ADH)

3. Types of hormones

4. 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

5. 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

6. 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

7. Steroids can be transformed to
active steroid in target cell

8. Steroid hormones
 Steroid hormones are no water soluble t 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

10. 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 estrdaiol.
 In the male, there is peripheral conversion of
testosterone to dihydrotestosterone (in
androgen target tissues, like muscle) and
estradiol (mostly in adipose tissue).

11.  Functions
 development of male secondary sex
characteristics; prevents bone resorption
Androgens
(strongest = testosterone)
(produced in testes primarily but weak
androgens in adrenal cortex) (anabolic steroid)

12.  an androgen, male sex hormone synthesized in the
testes, responsible for secondary male sex
characteristics, produced from progesterone
Testosterone

13. Androstenedione is the common final
precursor in the series of reactions
resulting in testosterone synthesis.

14. - produced from cholesterol primarily
by Leydig cells in testes
-secreted at adult levels during 1st trimester1,
during neonatal life, continually after puberty
-bound in plasma to albumin & sex hormone binding globulin
(SHBG)
- can be converted to the more potent, 5α-dihydrotestosterone
(DHT),
which is responsible for many of the responses to testosterone
in
the urogenital tract (e.g. prostate gland hyperplasia)
- binds to and activates a single androgen receptor (AR)
- androgen receptors are present in many tissues including
reproductive tissue, skeletal muscle, brain, kidney etc

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

16. 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).

17. 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

18. 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.

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

21. Steroid Hormones: Molecular Action

22. Control of testosterone production
 The production of testosterone by the leyding cells
is controlled indirectly by the hypothalamus, an
influence which is mediated from the
adenohypophysis
 This is control system theefore functions in two
stages , in first releating the cental nervous
syystem(hypothalamus) to the adenohypophysis,
and the second relating the adrenohypophysis to
the testes

23.  Testosterone can then be converted (mostly
in peripheral tissues) to:
- DHT (dihydrotestosterone) by 5a-reductase,
or to
-estradiol (E2) by cytochrome P450 aromatase
Testosterone Metabolism

24. The androgens, androstenedione and DHEA, circulate
bound primarily to sex hormone-binding globulin
(SHBG).
Although some of the circulating androgen is
metabolized in the liver, the majority of interconversion
occurs in the gonads (as described below), skin, and
adipose tissue.
DHEA is rapidly converted to the sulfated form, DHEA-S,
in the liver and adrenal cortex.

25. The primary biologically active metabolites of
the androgens are testosterone and
dihydrotestosterone which function by binding
intracellular receptors, thereby effecting
changes in gene expression and thereby,
resulting in the manifestation of the secondary
sex characteristics.

26. Biologic effects of testosterone
In the foetus, testosterone promotes
development of male reproductive
tract and external genitalia
(sex differentiation)
During puberty, testosterone
promotes development of :
• primary sexual characteristics
(e.g. enlargement of penis, scrotum and testes)
• secondary sexual characteristics
(e.g. male body shape, facial/pubic hair, deeper pitch of
voice)
• promotion of spermatogenesis

27. ->is a clinical diagnosis confirmed by hormone assays
-> is usually caused by
- underlying testicular disorders
high LH, but low testosterone levels
- hypothalamic-pituitary disorders,
low LH and low testosterone levels
-> if untreated, does not shorten life expectancy,
but is associated with significant morbidity.
ambiguous genitalia, delayed puberty & infertility
-> is treated by androgen replacement therapy (ART), usually
for the remainder of life. The aim is to restore tissue
androgen exposure by using the natural androgen
testosterone.
Androgen deficiency

28. Any Question ???

29. Thankyou

30. Medical Pharmacology Systems
IMED3328
Assoc Prof Peter Henry, Rm 1.34, Pharmacology
Peter.Henry@uwa.edu.au
Anabolic androgenic steroids
REFERENCE
Essential Endocrinology
John F Laycock & Peter H Wise
2nd edition