SOURCE , SYNTHESIS, METABOLISM AND

PHYSIOLOGICAL ROLE OF ANDROGENS

M.THILAKAR

LS 1154

4’th M.Sc. LIFE SCIENCES,

BDU.

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TESTOSTERONE

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DIHYDROTESTOSTERONE

ANDROGENS

TESTOSTERONESTestosterone is the principal androgen secreted by the mature testis.

Normal young men produce about 7 mg each day, of which less than 5% is derived from adrenalsecretions.

This amount decreases somewhat with age, so that by the seventh decade and beyond,testosterone production may have decreased to 4 mg per day, but in the absence of illness orinjury, As with the other steroid hormones, testosterone in blood is largely bound to plasmaprotein, with only about 2 to 3% present as free hormone.

About half is bound to albumin, and slightly less to sex hormone-binding globulin (SHBG), which isalso called testosterone-estradiol-binding globulin (TeBG).

This glycoprotein binds both estrogen and testosterone, but its single binding site has a higheraffinity for testosterone.

Its concentration in plasma is decreased by androgen Consequently, SHBG is more than twice asabundant in the circulation of women than men.

In addition to its functions as a carrier protein, SHBG may also act as an enhancer of hormoneaction.

BIOSYNTHESIS OF ANDROGEN

SITE : synthesized in the interstitial tissue by the leydig cells response to LH .

To a minor extent by adrenal glands in both the sexes.

Ovaries also produce a small amount of androgens

PRECURSOR: Cholesterol

It is first converted to pregnenolone by cytochrome p450 side chain cleavage enzyme which then forms androstenedione by two pathways:

1. Through progesterone (Progesterone (or ∆4) pathway)

2. Through 17-hydroxypregnenolone.(Dehydroepiandrosterone or ∆5 pathway)

HORMONAL CONTROL OF MALE REPRODUCTIVE SYSTEM

SYNTHESIS OF TESTOSTERONE IN TESTES

ENZYMES REQUIRED FOR THE PRODUCTION OF ANDROGENS

The conversion of pregnenolone to testosterone requires the action of five enzyme activities contained in three proteins:3β-hydroxyl steroid dehydrogenase (3β-HSD) and ∆5,4-isomerase;

17α-hydroxylase and C17-20 Lyase and

17β-hydroxyl steroid dehydrogenase (17β-OHSD).

The ∆5 route appears to be most used in human testes.

REGULATIONThe production of androgens is under the control of LH and FSH.

Regulated by feedback mechanism

The rate limiting step is the delivery of cholesterol to testosterone by StAR.

Steroidogenic acute protein (StAR)

DIAGRAMMATIC REPRESENTATION OF THE ANDROGEN SYNTHETIC PATHWAY IN THE LEYDIG CELLS OF THE TESTIS.

PREFERRED PATHWAYS ARE SHOWN BY HEAVY ARROWS. ONLY SMALL AMOUNTS OF DIHYDROTESTOSTERONE ARE

SYNTHESIZED FROM TESTOSTERONE WITHIN THE LEYDIG CELL.

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LH REGULATION OF LEYDIG CELLSLH binds to high affinity G protein-coupled plasma membrane receptors on Leydigcells.

Following binding, LH receptors aggregate, undergo a conformational change andbind Gs protein.

Guanosine triphosphate (GTP) then binds to Gsα subunit, displacing guanosinediphosphate (GDP), and Gsα binds and activates adenylate cylase resulting ingeneration of cyclic adenosine monophosphate (cAMP).

cAMP then binds to the regulatory subunits of protein kinase A, releasing activatedcatalytic subunits that phosphorylate a number of proteins in the Leydig cell andresult in stimulation of steroidogenesis and testosterone production

Both LH and hCG bind to the LH receptor and administration of high concentrationsof either hormone causes a decrease (down regulation) of LH receptor number andreduction in responsiveness to further stimulation by LH or hCG (desensitization).

In contrast to the suppression of pituitary LH production induced by continuoushigh-dosage GnRH administration, production of testosterone is not inhibited byhigh dosage LH or hCG administration, raising questions regarding the clinicalsignificance of LH receptor down regulation and Leydig cell desensitization.

FSH REGULATION OF SERTOLI CELL FUNCTION

FSH binds to high-affinity G protein-coupled plasma membrane receptors on Sertolicells.

Signal transduction follows a pathway that is analogous to that for LH with FSHreceptor binding leading to G protein activation of adenylate cyclase, generation ofcAMP that activates protein kinase A, followed by protein phosphorylation.

As with the regulation of LH receptors by LH or hCG, FSH administration also downregulates the number of FSH receptors on Sertoli cells, but the physiologicalsignificance of down-regulation is not known.

FSH binding has also been reported in rat spermatogonia, but direct effects of FSHon these stem cells

METABOLISM OF ANDROGEN

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FIRST PATHWAY :Involves oxidation at the 17 position,

Occurs in many tissues, including liver and produces 17-ketosteroids that are generally inactive or less active than the parent compound.

SECOND PATHWAY :Occurs primarily in target tissues

Dihydrotestosterone is Formed From Testosterone in Peripheral tissues.

Involves reduction of the A ring double bond and the 3 Ketosterone, a reaction catalyzed by the NADPH-dependent 5 α reductase

5 mg of testosterone is produced daily by testes. Approximately 400 µg of DHT is produced daily

Some estradiol is formed from the peripheral aromatization of testosterone.

TRANSPORT OF ANDROGENS

In the plasma testosterone and DHT bind to two proteins-1. Sex hormone binding globulin ( SHBG) binds 97 to 99% and

2. Testosterone-estrogen binding globulin( TEBG).

A small fraction is in free form.

Both these proteins are synthesized in liver.

The plasma testosterone level in normal men is about 0.7 µg/dl while in women it is < 0.1 µg/dl.

METABOLISM OF ANDROGEN

MODE OF ACTION

Both testosterone and dihydrotestosterone bind to a single class ofreceptors on the target tissues.

The affinity of DHT for the receptor is much higher compared totestosterone.

Receptor sites for androgens are found in muscle, brain, and other targettissues.

ANDROGEN ACTION

Diagrammatic representation of the metabolism oftestosterone. After secretion by the Leydig cell,testosterone travels through the plasma to the liveror target tissues. After metabolism and conjugation,products are excreted into the urine.

PHYSIOLOGICAL FUNCTIONS OF ANDROGEN

The androgens influence

1. Growth, development and maintenance of male reproductive organs.

2. Sexual differentiation and secondary sexual characteristics.

3. Spermatogenesis.

4. Male pattern of aggressive behavior.

5. Pubertal transformation:

Enlargement of testes, penis and scrotum.

Pubic and axillary hair.

Bone growth.

RBC mass increase.

Skeletal muscle mass increase.

Larynx enlarges - deepening of the voice

Increase in sebaceous glands - often cause of acne

Development of Beard

BIOCHEMICAL FUNCTIONS OF ANDROGEN

EFFECT ON PROTEIN METABOLISM:

Androgens promote

RNA synthesis( transcription)

Protein synthesis( translation).

Rapid growth of muscular-skeletal system associated with puberty.

EFFECT ON CARBOHYDRATE AND FAT METABOLISM :

Glycolysis,

Production of D-fructose from D-glucose by seminal vesicles.

Fatty acid synthesis and

Citric acid cycle.

EFFECTS ON MINERAL METABOLISM :

Androgens promote

Mineral deposition and bone growth

Kidney reabsorption of Na+, Cl- and water.

ABNORMALITIES ASSOCIATED WITH MALE SEX HORMONES

Hypogonadisn is a disorder characterized by a defect in testosterone synthesis.

It may be of two types.

1. PRIMARY HYPOGONADISM : is caused by a failure of testes to produce testosterone.

2. SECONDARY HYPOGONADISM : is due to an impairment in the release of gonadotropins.

ANDROGENS IN WOMEN

Because of a deficiency on both ovarian andadrenal androgens, some women withhypopituitarism have diminished libido despiteadequate estrogen therapy.

Although experience is limited, small doses of long-acting androgens (testosterone enanthate, 25-50mg intramuscularly every 4-8 weeks) may be helpfulin restoring sexual activity without causinghirsutism.

In addition, some reports have suggested that oraldehydroepiandrosterone (DHEA) in doses of 25 to50 mg/d may restore plasma testosterone levels tonormal.

A transdermal delivery system is being evaluatedfor use in women, but efficacy appears to bemodest and the long-term safety is unknown.

ANDROGENS IN MEN

The treatment of male hypogonadism.

Testosterone gels (available in packets in doses of2.5, 5, or 10 g, or from a metered-dose pump in1.25 g increments) and testosterone patches (indoses of 2.5 or 5 mg) are applied daily.

Other therapeutic preparations includeintramuscular testosterone enanthate or cypionatein doses of 100 mg every week or 200 mg every 2weeks.

Testosterone undecanoate is an intramuscularpreparation available in several countries that canbe given every 3 months.

Oral testosterone preparations available in theUnited States are rarely used out of concern forhepatic side effects.

REFERENCES

1. BASIC ENDOCRINOLOGY by H. Maurice Goodman – 4’th Ed (2009). Elsevier’s Science & Technology. [245-248]

2. ENDOCRINOOLOGY AT GLANCE by Ben Greenstein (1994). Blackwell sciences Ltd. [60-65]

3. GRETENSPAN'S BASIC & CLINICAL ENDOCRINOLOGY by Gardner D and Shoback – 9’th Ed(2011). The McGraw-Hill Companies

4. ENDOCRINOLOGY AND METABOLISM by Felig, Philip; Frohman, Lawrence A. – 4’th Ed (2001). The McGraw-Hill Companies

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