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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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TESTOSTERONE METABOLISM
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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TESTOSTERONE METABOLISM
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 METABOLISM
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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TESTOSTERONE METABOLISM
Type I 5 -reductase is produced in theliver
Type II is expressed in reproductivetissues and peripheral organs
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TESTOSTERONE METABOLISM
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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REGULATION OF TESTICULAR
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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REGULATION OF TESTICULAR
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
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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
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Ethinylestradiol
the estrogen in almost all
modern formulations of
combined oralcontraceptive pills
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Mestranol
the 3-methyl ether of
ethinylestradiol
It was the estrogenused in many of the
first oral
contraceptives
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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