GONADAL

HORMONES
 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
 TESTES
 Produces testosterone and spermatozoa
Cell types:
1. Spermatogonia – in seminiferous tubules
2. Leydig Cells (Interstitial cells)
located in connective tissues between the
seminiferous tubules
produce testosterone in response to LH
3. Sertoli cells
Form the basement membrane of the
seminiferous tubules and provide the
environment needed for germ cell maturation
Pathways of testosterone biosynthesis
 The pathway on the
left side of the figure is
called the ∆ 5 or
dehydroepiandro-
sterone pathway
 The pathway on the
right side is called the
∆ 4 or progesterone
pathway
 The asterisk indicates
that the 17
-hydroxylase and
17,20-lyase activities
reside in a single
protein, P450c17
Pathways of testosterone biosynthesis
 Of the 2 pathways, the
∆ 5 is preferred in
human testis
 The rate-limiting step,
like in the adrenal
gland, is the delivery of
cholesterol to the inner
mitochondrial
membrane by STAR
(steroidogenic acute
regulatory) protein
 The testes also produces 17β Estradiol
(E2)
 Most of the E2 produced by males is
derived from peripheral aromatization of
testosterone and androstenedione
TESTOSTERONE METABOLISM
Testosterone is metabolized by two pathways:
1. 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
2. Reduction of the A ring double bond and the 3-
ketone
less efficient and occurs primarily in target
tissues and produces the potent metabolite
dihydrotestosterone (DHT).
 CONVERSION OF
TESTOSTERONE TO DHT

About 50–100 µ g of DHT are secreted by the testes.

The rest is produced peripherally from testosterone in a
reaction catalyzed by the NADPH-dependent 5 α -
reductase
TESTOSTERONE METABOLISM

 The most significant metabolic product of

testosterone is DHT, since in many
tissues, including prostate, external
genitalia, and some areas of the skin, this
is the active form of the hormone
TESTOSTERONE METABOLISM

 The plasma content of DHT in the adult

male is about one-tenth that of
testosterone, and approximately 400 µ g
of DHT is produced daily as compared
with about 5 mg of testosterone
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
TESTOSTERONE METABOLISM

 Type I 5α -reductase is produced in the

liver
 Type II is expressed in reproductive
tissues and peripheral organs
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
 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
 Testosterone binds SHBG with higher
affinity than estradiol
 Increased SHBG causes an increase in
free estradiol:testosterone ratio
 An increase in free estradiol levels can
cause gynecomastia (breast enlargement)
 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
 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 maintain
spermatogenesis
 REGULATION OF TESTICULAR
ACTION
 Inhibin is a peptide that is an inhibitor of FSH
synthesis and secretion
 Inhibin contains an alpha and beta subunit linked
by disulfide bonds. Two forms of inhibin differ in
their beta subunits (A or B), while their alpha
subunits are identical
 Inhibin is secreted from the sustentacular cell,
located in the seminiferous tubule inside the
testes
EFFECTS OF ANDROGENS
1. Sexual differentiation
2. Spermatogenesis
3. Development of secondary sexual
organs
4. Anabolic metabolism and gene
regulation
5. Male-pattern behavior
 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
 ANDROGEN DEFECTS
2. Hypogonadism
 Decreased testosterone
 May be primary (testicular failure) or
secondary (defective gonadotropin
secretion)
 ANDROGEN DEFECTS
3. Testicular feminization
 Receptor dysfunction
 Feminized external genitalia
FEMALE
HORMONES
 17-beta-estradiol is the primary estrogen from
the ovary
 In pregnancy, more estriol is produced by the
placenta
 Estrogens are formed by the aromatization of
androgens through hydroxylation
 Estrogen secretion is stimulated by FSH from
the pituitary
•Each hydroxylation requires oxygen
and NADPH
•Estradiol is formed from testosterone
•Estrone is formed from androstene-
dione
 The theca cells of the ovary are the source
of androstenedione and testosterone
 Progesterone is produced and secreted by
the corpus luteum, which also makes
some estradiol
 As much as 50% of Estradiol produced
during pregnancy is from androgens
Biosynthesis of progesterone in the
corpus luteum
 As much as 50% of Estradiol produced during
pregnancy is from androgens
 The conversion of androstenedione to estrone is
the major source of estrogens in
postmenopausal women
 Aromatase is present in adipose tissue, liver,
and skin, and increased activity occurs in liver
cirrhosis, hyperthyroidism, aging and obesity
 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 or
DHT
 Progesterone and cortisol have equal affinity to CBG
 The metabolic clearance is inversely related to SHBG
affinity, so estradiol is more rapidly cleared than
testosterone or DHT
 Ovarian steroids are not stored; they are secreted
immediately upon synthesis
 METABOLISM
 The liver converts estradiol and estrone to
estriol, 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 rapid
metabolism
 Na-pregnanediol-20-glucuronide is the
metabolite of progesterone in urine
 Certain synthetic steroids have
progestational activity and avoid hepatic
metabolism, making them useful as oral
contraceptives (e.g. 17α -
hydroxyprogesterone)
FUNCTIONS OF OVARIAN
HORMONES
 Prepare for reproduction by:
1. Maturing the primordial germ cells
2. Developing tissues to allow implantation of
blastocyst
3. Provides hormonal timing for ovulation
4. Prepares environment needed for pregnancy
5. Influences parturition and lactation
 Under estrogen stimulation:
1. Vaginal epithelium proliferates
2. Uterine endothelium proliferates
3. Uterine glands hypertrophy
4. Myometrium develops an intrinsic, rhythmic
motion
5. Breast ducts proliferate
- Estradiol has anabolic effects on bone and
cartilage
- Estrogen causes vasodilation and heat
dissipation
EFFECT OF PROGESTINS
1. Reduce proliferation of vaginal epithelium
2. Convert uterine epithelium from proliferative to
secretory
3. Prepare for implantation of zygote
4. Enhance development of acinar portion of
breast glands
5. Decrease peripheral blood flow resulting in
increased body temperature
 THE MENSTRUAL CYCLE
 Only human beings and great apes
experience a true menstrual cycle; that is,
they are POLYESTROUS (ovulate and
mate several times in a year)
 The cycle usually takes 25-35 days
(average: 28 days)
Name of phase Days

menstrual phase 1-4

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

Variations in cycle length are always due to this phase

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 secretory 27-28

phase)
 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 cramps
during this time. (dysmenorrhea)
 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 pituitary
gland
 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 to
ovulation
 Luteal Phase
 After ovulation, the granulosa cells of the
ruptured follicle luteinize and form the
corpus luteum, which produces
progesterone and some estradiol
 Estradiol peaks midway through the luteal
phase, then declines
 Progesterone prepares and maintains the
secretory endothelium
 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
THE MENSTRUAL CYCLE
PLACENTAL
HORMONES
 Progestins
 Molecules that bind to the progesterone
receptor
 Support the endometrium to provide an
environment conducive to fetal survival
 Progesterone and other progestins also
potently inhibit secretion of the pituitary
gonadotropins LH and FSH, preventing
ovulation from occurring
 Estrogen
 Maternal estrogen levels are often a useful
indicator of fetal well being
 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 maternal
recognition of pregnancy
 Placental protein hormones
 Placental lactogens
The functions of placental lactogens are not well
understood
Thought to modulate fetal and maternal metabolism,
perhaps mobilizing energy substrates for fetal use
 Relaxin

Thought to act synergistically with progesterone to maintain

pregancy
Causes relaxation of pelvic ligaments at the end of
gestation and may therefore aid in parturition.
 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
 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 suckling
also stimulates oxytocin causing milk expulsion
 MENOPAUSE
 Loss of all follicles and ovarian estrogen
production
 Estrone may be produced by peripheral
aromatization of androstenedione
 Marked increase in LH and FSH
 Atrophy of the urinary tract and vaginal
epithelium
 Decrease in bone mass (osteoporosis)
SYNTHETIC
HORMONES
 Most synthetic hormones are synthesized
to retard hepatic metabolism for oral
administration (decrease 1st pass effect)
 an orally active synthetic
nonsteroidal estrogen that
was first synthesized in
1938
 In 1971 it was found to be a
teratogen when given to
pregnant women
 Of limited use today due to
increased risk for breast
cancer
Ethinylestradiol
 the estrogen in almost all
modern formulations of
combined oral
contraceptive pills
Mestranol
 the 3-methyl ether of
ethinylestradiol
 It was the estrogen
used in many of the
first oral
contraceptives
Clomiphene citrate
 acts by inhibiting the action of estrogen on the
gonadotrope cells in the anterior pituitary gland
 "Sensing" low estrogen levels, FSH release is
increased, leading to a higher rate of ovulation
and hence pregnancy
 Can lead to multiple ovulation, and hence
increasing the chance of twins
 There may be an increased risk of ovarian
cancer, and weight gain.
NAFOXIDINE AND TAMOXIFEN

 Combine with estrogen receptor to form

stable complexes with chromatin
 Receptor cannot recycle, resulting in
estradiol inhibition
 Used in the treatment of estrogen
receptor-dependent breast cancer
SERMs (Selective Estrogen
Receptor Modulators)
 A derivative of tamoxifen
 block the action of
estrogen in the breast
and certain other tissues
by occupying estrogen
receptors inside cells
 For tx of osteoporosis
Norethindrone Medroxyprogesterone
Acetate

 Progestin used as  Given IM for the

treatment of
an oral endometrial CA
contraceptive  Inhibits ovulation
PATHOPHYSIOLOGY
 Primary hypogonadism
 Decreased ovulation and/or decreased
hormone production
 Secondary hypogonadism
 Loss of pituitary gonadotropin function
 GONADAL DYSGENESIS
 Turner’s syndrome
 XO karyotype
 Female internal and external genitalia
 Developmental abnormalities
 Delayed pubery
Polycystic Ovarian Syndrome
 Stein-Leventhal syndrome
 Androgen overproduction
 Hirsutism, obesity, irregular menses,
decreased fertility
 Hydatidiform mole, choriocarcinoma
increased hCG
 Leydig cell tumors, Arrhenoblastoma
increased testosterone
 Granulosa Theca Cell Tumors
Increased estrogen
 Intraovarian adrenal rests
Increased cortisol levels