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Objectives

1. Illustrate the biosynthetic steps of sexhormones.

2. Identify the mechanism of sex hormoneregulation.

3. Recognize the most potent forms of sexhormones and its production.

4. Identify the transportation of sex hormones.

5. Point out the disturbance of sex hormones incase of obesity.

6. Identify the degradation of sex hormones.

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Steroid Hormone Biosynthesis dependence

1. its complement of peptidehormone receptors,2. itsresponse to peptide hormone stimulation and

3. itsgenetically expressed enzymes.

The following indicates which peptide hormone is responsible for stimulatingthe synthesis of which steroid hormone:

Luteinizing Hormone (LH) progesterone and testosterone

Follicle Stimulating Hormone (FSH)

Estradiol

Steroid hormones have relatively long plasma half-lives, usually ranging from 1to 2 hours. These hormones travel to their site of action and diffuse throughthe lipid bilayer cell membrane to reach the specific intracellular receptor

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Sex steroid-Hormones

Biosynthesis

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Adrenal gland

Adrenocortical H

GONADAL (SEX)H Adrenalin

Noradrenalin

Dopamine 3/12/20145

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Cholesterol and Steroids

The ultimate precursor of all steroids is acetyl-CoA, then cholesterol.The conversion of cholesterol to the 18-, 19-, and 21-carbon steroid hormones

involves:

the rate-limiting, irreversible cleavage of a 6-carbon residue from cholesterol,

producing pregnenolone , the precursor of many important steroids.(requires 3NADPH and 3O2)

Steroids with 21 C-atoms are known as pregnanes.

Steroids with 19 and 18 C-atoms are known as androstanes and estranes,

respectively.

Retinoic acid and vitamin D are not derived from pregnenolone, but from

vitamin A and cholesterol respectively.

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Synthesis of the various adrenal steroid

hormones from cholesterol. Only the terminal

hormone structures are included. 3b-DH is 3b-

dehydrogenase, P450c11 is 11b-hydroxylase,

P450c17 is 17a-hydroxylase, P450c21 is

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The first reaction (rate limiting step, regulated step)

Converting cholesterol to C18, C19 and C21 steroids involves thecleavage of a 6-carbon group from cholesterol.

This cleavage step is catalyzed by an enzyme hydroxylatingsystem known as P450-linked side chain cleaving enzyme, amitochondrial cytochrome P450 oxidase CYP11A (P450scc), or(20,22desmolase in adrenal cortex), found in the mitochondria ofsteroid-producing cells, but not in significant quantities in other

cells.

In Gonads, The activity of each of these components is increasedby both cAMP- and PKA-dependent processes.

Regulation of Sex H Biosynthesis

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cAMP stimulates PKA, leading to the phosphorylation of a cholesteryl-ester esterase

and generating increased concentrations of cholesterol, the substrate for P450scc (or

desmolase in adrenals).

long-term regulation is effected at the level of the gene for P450scc. This gene

contains a cAMP regulatory element (CRE) that binds cAMP and increases the level of

P450scc RNA transcription, thereby leading to increased levels of the enzyme.

Finally, cholesterol is a negative feedback regulator of HMG CoA reductase activity.

Thus, when cytosolic cholesterol is depleted, de novo cholesterol biosynthesis is

stimulated.

Subsequent to P450scc activity, produced pregnenolone moves to the cytosol, where

further processing depends on the cell (tissue) under consideration.

Mechanism of Steroid Hormone Regulation in Gonads

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Testosterone and

Estrogen

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Testicular Steroidogenesis Testicular androgens are synthesized in the interstitial tissue by

the leydig cells.

The immediate precursor of gonodal steroids is cholesterol

(like adrenal).

The rate limiting stepas in adrenal- is the delivery of cholesterol to

the inner membrane of mitochondria by the transport protein

StAR.

P450scc catalyze the conversion of cholesterol into

pregnenolone (like in ovary and adrenal).

The reaction is regulated in ovary and testis by LH, while in

the adrenal by ACTH.

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Conversion of pregnenolone into

testosterone

The formation of testosterone from

pregnenolone may be thru progesteronepathway (or 4) or DHEA pathway (or 5)

(most common in testes).

The seq of testosterone formation from

pregnenolone requires 5 enzymescontained in 3 protein complexes located

in mitochondria:-

3-hydroxysteroid dehydrogenase (3-

OHSD) and 5,4

-isomerase; 17-hydroxylase and 17,20-lyase; and

17-hydroxysteroid dehydrogenase (17-

OHSD), increased by LH.

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Metabolism of Testosterone

Testosterone is metabolized by 2 pathways:-

1. Involves the oxidation at 17 position (occurs in many

tissues and liver) producing inactive metabolite (17-ketosteroids).

2. Involves reduction of ring-double bond (occurs in

target tissues*) producing potent metabolite DHT.

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Di-hydro-testosterone DHT (DHT) is the most significant metabolic product (potent) of

testosterone.

DHT is the active form of testosterone.

Plasma conc of DHT in males is 1/10 of testosterone conc (400ugversus 5mg daily production).

About 100ug of DHT are secreted by testes, while the rest fromthe testosterone reaches the peripheral tissues thru 5--reductaseand NADPH.

The tesosterone is cosidered as pro-hormone.

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

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Testosterone and DHT are carried (in addition to estradiol) in

the plasma, and delivered to target tissue, by a specific gonadal-steroid binding globulin (GBG called SHBG) which is secreted

under influence of FSH.

The majority of serum testosterone(97%) is bound totransporter proteins

sex hormone binding globulin (SHBG),

but it is also exist loosly bound to albumin

and in the free state. N.B. :analyzed as free and totaltestosterone.

So, "Hypogonadism is defined as a free testosterone level that is

below the lower limit of normal for young adult control.

Testosterone and DHT transport

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SHBG

It is a liver-delivered glycoprotein

Testosterone and Estradiol circulate bound to:

SHBGof higher affinity for Testosterone .

Estradiol stimulates synthesis of SHBG in liver while,

testosterone decrease it Hence, SHBG conc. is twice-conc in females .

SHBG : Estradiol like effect and androgenlike effect

i.e Serum SHBG concentrations are controlled by androgens

(decrease), estrogens (increase), and insulin (decrease) .

hyperthyroidism (like estrogen) increase SHBG, while,

hypothyroidism and advancing age (like androgens) decrease

SHBG.

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Testosterone regulation

1. The amount of testosterone synthesized is regulated by the hypothalamic-pituitary-testicular axis (GnRH) and the pituitary release, LH, and FSH.

2. Estradiol rather than testosterone serves as the most important feedback signal

to the hypothalamus and pituitary.

Zinc deficiency lowers testosterone levels.

(In men, inappropriately high levels of estrogens decrease testosterone).

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Estrogens are formed by the aromatization of androgens in a complexprocess that involves 3 hydroxylation steps, each of which requires O2and NADPH.

The aromatase enzyme complex is thought to include a P450monooxygenase.

Estradiol is formed if the substrate of this enzyme complex is testosterone,whereas estrone results from the aromatization of androstenedione.

In some species, estrone,synthesized in numerous tissues, is moreabundant.

Significant amounts of estrogens are produced by the peripheralaromatization of androgens.

In females, adrenal androgens are important sources of estrogens, sinceas much as 50% of the estrogens produced during pregnancy comes fromthe aromatization of androgens.

OvariansteroidogenesisEstrogens

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Estrogens in postmenopause, pregnant, and

Males

In post- menopausal women, conversion of androstenedione to

estrone is the major source of estrogens.

In pregnancy, relatively more Estriol is produced (represents 90% of

circulating estrogen), and this comes from the placenta.

In human males, the peripheral aromatization of testosterone to

estradiol (E2) accounts for 80% of the production of the E2.

Progesterone, a precursor for all steroid hormones, is produced and

secreted by the corpus luteum as an end-product hormone

because these cells do not contain the enzymes necessary toconvert progesterone to other steroid hormones.

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17--Estradiol Estradiol is a natural estrogen produced when the substrate is testosterone.

mostly present in serum bound to protein (97-99%) and in free state.In females, estradiol is secreted by ovary and corpus luteum.

In males, minute amounts are secreted by testis and adrenal cortex, while 80% from the

peripheral tissue conversion of testosterone.

Aromatase activity is also found in granulosa cells, but in these cells the activity is

stimulated by FSH.

Endometrial growth is stimulated by estradiol and progesterone in preparation for

implantation of fertilized egg. If conception doesnt occur estradiol and progesterone

decrease initiating menses.

Levels of estradiol is useful in monitoring ovulatory status reflect follicular maturation. And

in assessment of sexual dev and causes of infertilitry and menopause.

Abnormal levels in males are indicative of feminizing syndrome like gynecomastia.

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Estrogen Biosynthesis In females, LH binds to thecal cells of the ovary, where it stimulates the

synthesis of androstenedione and testosterone by the usual cAMP- and PKA-

regulated pathway.

An additional enzyme complex known as aromatase is responsible for the

final conversion of androstenedione and testosterone into the estrogens.

(aromatization)

Aromatase is a complex endoplasmic reticulum enzyme found in the ovary

and in numerous other tissues in both males and females.

Aromatase action involves hydroxylations and dehydrations that culminate inaromatization of the A ring of the androgens.

Estriol comprises 90% of circulating estrogen in normal pregnancy. And is

formed from DHEA-S that formed by adrenals and passes to placenta where

it converts to estriol and enters the maternal blood.

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Aromatase activity is present in adipose cellsand also in liver, skin, and increased in somediseases like hyperthyroidism, aging, and

obesity.

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Degradation of steroid hormones

sterane skeleton is very stable and it is unable to be

destroyed.

reduction is included in inactivation of steroids

(hydrogenation of double bond) in ring A.

Testosterone androsterone and etiocholanolone

Estrogen estriol or 2-hydroxyesterone, a catechol estrogen

inactivation reactions occur in liver

conjugation with glucuronic acid or sulphuric acid formed conjugates are excreted with urine

(ketosteroids)