gonadal hormones 1-13

8/14/2019 Gonadal Hormones 1-13

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GONADAL

HORMONES


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Gonads are bifunctional organs that

produce germ cells and sex hormones

They play a role in reproduction and

contraception

They also have anabolic functions on the

skin, bones, and muscles


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TESTES Produces testosterone and spermatozoa

Cell types:

1. Spermatogonia in seminiferous tubules

2. Leydig Cells (Interstitial cells)located in connective tissues between theseminiferous tubules

produce testosterone in response to LH

3. Sertoli cells

Form the basement membrane of theseminiferous tubules and provide theenvironment needed for germ cell maturation


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Pathways of testosterone biosynthesis The pathway on the

left side of the figure iscalled the 5 ordehydroepiandro-

sterone pathway The pathway on the

right side is called the 4 orprogesteronepathway

The asterisk indicates

that the 17-hydroxylase and17,20-lyase activitiesreside in a singleprotein, P450c17


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Pathways of testosterone biosynthesis

Of the 2 pathways, the

5 is preferred inhuman testis

The rate-limiting step,

like in the adrenal

gland, is the delivery ofcholesterol to the inner

mitochondrial

membrane by STAR

(steroidogenic acute

regulatory) protein


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The testes also produces 17 Estradiol(E2)

Most of the E2 produced by males is

derived from peripheral aromatization of

testosterone and androstenedione


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TESTOSTERONE METABOLISM

Testosterone is metabolized by two pathways:

1. Oxidation at the 17 position

occurs in many tissues, including liver, andproduces 17-ketosteroids that are generallyinactive or less active than the parentcompound

2. Reduction of the A ring double bond and the 3-

ketoneless efficient and occurs primarily in targettissues and produces the potent metabolitedihydrotestosterone (DHT).


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CONVERSION OF

TESTOSTERONE TO DHT

About 50100 g of DHT are secreted by the testes.The rest is produced peripherally from testosterone in a

reaction catalyzed by the NADPH-dependent 5 -

reductase


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The most significant metabolic product of

testosterone is DHT, since in many

tissues, including prostate, externalgenitalia, and some areas of the skin, this

is the active form of the hormone


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The plasma content of DHT in the adult

male is about one-tenth that of

testosterone, and approximately 400 gof DHT is produced daily as compared

with about 5 mg of testosterone


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Testosterone can thus be considered a

prohormone, since it is converted into a

much more potent compound(dihydrotestosterone) and since most of

this conversion occurs outside the testes


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Type I 5 -reductase is produced in theliver

Type II is expressed in reproductivetissues and peripheral organs


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17-ketosteroid metabolites androsterone

and etiocholarolone are conjugated with

glucuronide and sulfate in the liver 1-5% of testosterone is aromatized to

estradiol


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SEX HORMONE-BINDING

GLOBULIN (SHBG) Also called testosterone-estrogen-binding

globulin (TEBG)

Produced by the liver

Production is increased by estrogen, liver

disease, and hyperthyroidism

Decreased by androgens, advanced age,

and hypothyroidism


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Testosterone binds SHBG with higher

affinity than estradiol

Increased SHBG causes an increase infree estradiol:testosterone ratio

An increase in free estradiol levels can

cause gynecomastia (breast enlargement)


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REGULATION OF TESTICULAR

ACTION LH stimulates steroidogenesis by binding

to membrane receptors of Leydig cells and

activating adenylate cyclase This enhances STAR and P450 scc

leading to increased steroid synthesis


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ACTION FSH enhances the production of

androgen-binding protein (ABP) by the

Sertoli cells of the testes Androgen binding protein is essential to

concentrating testosterone in levels high

enough to initiate and maintainspermatogenesis


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ACTION Inhibin is a peptide that is an inhibitor of FSH

synthesis and secretion

Inhibin contains an alpha and beta subunit linkedby disulfide bonds. Two forms of inhibin differ intheir beta subunits (A or B), while their alphasubunits are identical

Inhibin is secreted from the sustentacular cell,located in the seminiferous tubule inside thetestes


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EFFECTS OF ANDROGENS

1. Sexual differentiation

2. Spermatogenesis

3. Development of secondary sexualorgans

4. Anabolic metabolism and gene

regulation5. Male-pattern behavior


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ANDROGEN DEFECTS

1. Benign Prostatic Hypertrophy (BPH)

Due to increased DHT or testosterone

particularly in older males

Leads to difficulty in urination due to

obstruction of the urethra

Different form prostatic cancer


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ANDROGEN DEFECTS

2. Hypogonadism

Decreased testosterone

May be primary (testicular failure) or

secondary (defective gonadotropin

secretion)


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ANDROGEN DEFECTS

3. Testicular feminization

Receptor dysfunction

Feminized external genitalia


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FEMALE

HORMONES


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17-beta-estradiol is the primary estrogen from

the ovary

In pregnancy, more estriol is produced by theplacenta

Estrogens are formed by the aromatization of

androgens through hydroxylation

Estrogen secretion is stimulated by FSH from

the pituitary


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Each hydroxylation requires oxygenand NADPH

Estradiol is formed from testosteroneEstrone is formed from androstene-

dione


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The theca cells of the ovary are the source

of androstenedione and testosterone

Progesterone is produced and secreted bythe corpus luteum, which also makes

some estradiol

As much as 50% of Estradiol producedduring pregnancy is from androgens


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Biosynthesis of progesterone in the

corpus luteum


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As much as 50% of Estradiol produced during

pregnancy is from androgens

The conversion of androstenedione to estrone isthe major source of estrogens in

postmenopausal women

Aromatase is present in adipose tissue, liver,

and skin, and increased activity occurs in livercirrhosis, hyperthyroidism, aging and obesity


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PLASMA TRANSPORT Estrogens are bound to sex hormone-binding globulin

(SHBG) Progestins are bound to corticosteroid-binding globulin

produced by the liver

SHBG binds estradiol 5x less avidly than testosterone orDHT

Progesterone and cortisol have equal affinity to CBG The metabolic clearance is inversely related to SHBG

affinity, so estradiol is more rapidly cleared thantestosterone or DHT

Ovarian steroids are not stored; they are secretedimmediately upon synthesis


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METABOLISM

The liver converts estradiol and estrone toestriol, all of which are substrates for

glucuronidation or sulfation The liver cannot metabolize estrognes

rapidly, so they are effective as oral drugs In contrast, progesterone is ineffective

when given orally due to its rapidmetabolism


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Na-pregnanediol-20-glucuronide is the

metabolite of progesterone in urine

Certain synthetic steroids haveprogestational activity and avoid hepatic

metabolism, making them useful as oral

contraceptives (e.g. 17 -hydroxyprogesterone)


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FUNCTIONS OF OVARIAN

HORMONES Prepare for reproduction by:

1. Maturing the primordial germ cells

2. Developing tissues to allow implantation ofblastocyst

3. Provides hormonal timing for ovulation

4. Prepares environment needed for pregnancy5. Influences parturition and lactation


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Under estrogen stimulation:

1. Vaginal epithelium proliferates

2. Uterine endothelium proliferates

3. Uterine glands hypertrophy

4. Myometrium develops an intrinsic, rhythmicmotion

5. Breast ducts proliferate- Estradiol has anabolic effects on bone and

cartilage- Estrogen causes vasodilation and heat

dissipation


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EFFECT OF PROGESTINS

1. Reduce proliferation of vaginal epithelium

2. Convert uterine epithelium from proliferative to

secretory3. Prepare for implantation of zygote

4. Enhance development of acinar portion of

breast glands

5. Decrease peripheral blood flow resulting in

increased body temperature


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THE MENSTRUAL CYCLE

Only human beings and great apes

experience a true menstrual cycle; that is,

they are POLYESTROUS (ovulate andmate several times in a year)

The cycle usually takes 25-35 days

(average: 28 days)

Name of phase Days


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Name of phase Days

menstrual phase 1-4

follicular phase (also known as proliferative phase) 5-13

ovulation (not a phase, but an event dividing phases) 14

luteal phase (also known as secretory phase) 15-26

ischemic phase (some sources group this with secretoryphase)

27-28

Variations in cycle length are always due to this phase


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Menstrual Phase

The average blood loss during

menstruation is 35 millilitres with 10-80 mL

considered normal An enzyme called plasmin tends to inhibit

the blood from clotting

Many women experience uterine crampsduring this time. (dysmenorrhea)


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Follicular Phase

Progressive increase in estrogen, low

progesterone levels

LH peak heralds its end Continual high estrogen in contraceptives

suppresses FSH and LH release and

inhibits the action of GnRH on the pituitarygland


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Ovulation

When the ovarian follicle has matured, it

secretes enough estradiol to trigger the acute

release of LH In the average cycle this LH surge starts around

cycle day 12 and may last 48 hours

The release of LH matures the egg and weakens

the wall of the follicle in the ovary, leading toovulation


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Luteal Phase

After ovulation, the granulosa cells of theruptured follicle luteinize and form the

corpus luteum, which producesprogesterone and some estradiol Estradiol peaks midway through the luteal

phase, then declines Progesterone prepares and maintains the

secretory endothelium


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Luteal Phase

LH is required to maintain the corpus luteum

If implantation of the fertilized egg occurs, LH

function is assumed by hCG from the placenta Without implantation, corpus luteum regresses

and menstruation ensues


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THE MENSTRUAL CYCLE
http://upload.wikimedia.org/wikipedia/commons/f/f0/MenstrualCycle.png


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PLACENTAL

HORMONES


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Progestins

Molecules that bind to the progesteronereceptor

Support the endometrium to provide anenvironment conducive to fetal survival

Progesterone and other progestins alsopotently inhibit secretion of the pituitarygonadotropins LH and FSH, preventingovulation from occurring


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Estrogen

Maternal estrogen levels are often a useful

indicator of fetal well being


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Placental protein hormones

Chorionic gonadotropins (hCG)

-produced by fetal trophoblast cells

-binds to the luteinizing hormone receptor

on cells of the corpus luteum, which

prevents luteal regression

-serves as the signal for maternalrecognition of pregnancy


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Placental protein hormones

Placental lactogens

The functions of placental lactogens are not wellunderstood

Thought to modulate fetal and maternal metabolism,perhaps mobilizing energy substrates for fetal use

Relaxin

Thought to act synergistically with progesterone to maintain

pregancyCauses relaxation of pelvic ligaments at the end of

gestation and may therefore aid in parturition.


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PARTURITION

The act of giving birth to a child

Trigger is unknown

Oxytocin stimulates uterine contractility

but will not initiate labor unless pregnancy

is at term


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MAMMARY GLAND

DEVELOPMENT Stimulated by estrogen (ductal growth),

progestin (alveolar proliferation), and prolactin

(lactation) Progesterone inhibits milk production and

secretion, and its abrupt decrease after delivery

causes lactation

Prolactin is stimulated by suckling, and sucklingalso stimulates oxytocin causing milk expulsion


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MENOPAUSE

Loss of all follicles and ovarian estrogen

production

Estrone may be produced by peripheralaromatization of androstenedione

Marked increase in LH and FSH

Atrophy of the urinary tract and vaginal

epithelium

Decrease in bone mass (osteoporosis)


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SYNTHETIC

HORMONES


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Most synthetic hormones are synthesized

to retard hepatic metabolism for oral

administration (decrease 1st

pass effect)


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an orally active synthetic

nonsteroidal estrogen thatwas first synthesized in

1938

In 1971 it was found to be a

teratogen when given topregnant women

Of limited use today due to

increased risk for breast

cancer
http://en.wikipedia.org/wiki/Image:DES_structure.png


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Ethinylestradiol

the estrogen in almost all

modern formulations of

combined oralcontraceptive pills
http://upload.wikimedia.org/wikipedia/commons/8/8d/Ethinylestradiol-2D-skeletal.png


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Mestranol

the 3-methyl ether of

ethinylestradiol

It was the estrogenused in many of the

first oral

contraceptives
http://upload.wikimedia.org/wikipedia/commons/7/7d/Mestranol.svg


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Clomiphene citrate

acts by inhibiting the action of estrogen on thegonadotrope cells in the anterior pituitary gland

"Sensing" low estrogen levels, FSH release isincreased, leading to a higher rate of ovulationand hence pregnancy

Can lead to multiple ovulation, and henceincreasing the chance of twins

There may be an increased risk of ovariancancer, and weight gain.


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NAFOXIDINE AND TAMOXIFEN

Combine with estrogen receptor to form

stable complexes with chromatin

Receptor cannot recycle, resulting inestradiol inhibition

Used in the treatment of estrogen

receptor-dependent breast cancer

SERM (S l ti E t


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SERMs (Selective Estrogen

Receptor Modulators)

A derivative of tamoxifen

block the action of

estrogen in the breastand certain other tissues

by occupying estrogen

receptors inside cells

For tx of osteoporosis


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Norethindrone

Progestin used as

an oralcontraceptive

Medroxyprogesterone

Acetate

Given IM for thetreatment ofendometrial CA

Inhibits ovulation


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PATHOPHYSIOLOGY


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Primary hypogonadism

Decreased ovulation and/or decreased

hormone production


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Secondary hypogonadism

Loss of pituitary gonadotropin function


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GONADAL DYSGENESIS

Turners syndrome

XO karyotype

Female internal and external genitalia

Developmental abnormalities

Delayed pubery


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Polycystic Ovarian Syndrome

Stein-Leventhal syndrome

Androgen overproduction

Hirsutism, obesity, irregular menses,decreased fertility


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Hydatidiform mole, choriocarcinoma

increased hCG

Leydig cell tumors, Arrhenoblastomaincreased testosterone Granulosa Theca Cell Tumors

Increased estrogen

Intraovarian adrenal restsIncreased cortisol levels

gonadal hormones 1-13

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