Synthesis of Testosterone

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Synthesis of Testosterone
Testosterone is one of the androgens hormones that is synthesized in interstitial tissues by leydig cells.
The precursor of gonadal steroids (as we know before that testosterone is steroid hormone) is cholesterol.
The rate-limiting step in synthesis of testosterone is delivery of cholesterol to the inner mitochondrial membrane by the transport protein StAR*.
*An ACTH-dependent steroidogenic acute regulatory (StAR) protein is essential for the transport of cholesterol to P450scc in the inner mitochondrial membrane.
Once cholesterol is in the proper location, it is acted upon by side chain cleavage enzyme P450scc to be converted into Pregnenolone. This step is identical in adrenal and tests, however in testis, the reaction is promoted by LH not ACTH.
Conversion of Pregnenolone to Testosterone is done by 5 enzyme activities:
a)    3β-hydroxysteroid dehydrogenase (3β-OHSD) and Δ5,4-isomerase are found in sER; which i) converts Pregnenolone to Progesterone, ii) converts 17 alpha- hydroxypregnenolone to 17 alpha-hydroxyprogesterone, iii) converts dehydroepiandrosterone (DHEA) into Androstenedione, iv) converts Δ5 Androstenediol into Testosterone.
b)   17α-hydroxylase which; i) converts Pregnenolone into 17 alpha- hydroxypregnenolone, ii) converts Progesterone into 17 alpha-hydroxyprogesterone.
c)    17,20-lyase which; i) converts 17 alpha- hydroxypregnenolone into dehydroepiandrosterone (DHEA), ii) converts 17 alpha-hydroxyprogesterone into Androstenedione.
d)   17β-hydroxysteroid dehydrogenase (17β-OHSD) found in sER which; i) converts dehydroepiandrosterone (DHEA) into Androstenediol, ii) converts Androstenedione into Testosterone. And these reactions are reversible.

So, summary:


Pathway on left side in the photo is called dehydroepiandrosterone (or Δ5) pathway which is common in human testis.
Pathway on right side in the photo is called progesterone (or Δ4) pathway.

 So, don’t forget first step of conversion of cholesterol into pregnenolone!!!!!!!

Fate of testosterone:

Testosterone is metabolized in 2 pathways:
Oxidation at 17 position
Reduction at A ring double bond and 3-ketone group.
Occurs in many tissues, including liver, and produces 17-ketosteroids that are generally inactive or less active than the parent compound.
is less efficient, occurs primarily in target tissues and produces the
potent metabolite DHT.

Some estradiol is formed from the peripheral aromatization of
testosterone, particularly in males.

DHT:  
1)    The most significant metabolic product of testosterone is DHT, since in
many tissues, including prostate, external genitalia, and some areas of skin.
2)    The plasma content of DHT in the adult male is about one-tenth that of testosterone, and ~400 μg of DHT is produced daily as compared with about 5 mg of testosterone.
3)    About 50 to 100 μg of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH dependent 5α-reductase as you can see in the figure. 


Regulation of Testosterone:



See you later, in another topic in Biochemistry!!!!!!!

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