- Overview
- Testes --
gametogenic/endocrine
functions
- Gametogenic: FSH-dependent (pituitary
secretion)
- Androgens
(high concentrations):
required for sperm
production in
seminiferous tubules
- Sertoli
cells in seminiferous
tubules: source for
testicular estradiol
- With
LH stimulation:
- androgens synthesized in
interstitial/Leydigcells
between seminiferous
tubules
- Sertoli
cell synthetic products
and secretions:
- mullerian duct inhibitory
factor
- inhibin-- feedback
inhibition (with
dihydrotestosterone) of
pituitary FSH secretion
- activin--stimulates
pituitary FSH release
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Androgen/Anabolic
Steroids
- Introduction:androgens/anabolic
steroids
- Most important androgen:
testosterone
- Leydig cells account for 95%
of synthesis
- Adrenal: 5%
- Also secreted by the
testes:
dihydrotestosterone (potent
androgen)-
androstenedione
-
dehydroepiandrosterone
- pregnenolone
-- small amounts; along with
17-hydroxylation derivatives
- progesterone
-- small amounts; along with
17-hydroxylation derivatives
- 65% of circulating
testosterone: bound to sex
hormone-binding globulin (SHBG)
- 33% of circulating
testosterone: bound to albumin
- 2% -- free; they enter
cells; bind to intracellular receptors
- Factors that increase SHBG:
- thyroid hormone
- estrogen
- increased in patients
with liver cirrhosis
- Factors that decreases SHBG:
- androgen
- growth hormone
- obesity
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- Metabolism:androgens
& anabolic steroids:
- In many peripheral
tissues:testosterone converted to
dihydrotestosterone by 5-a reductase
- in these
peripheral tissues: major
androgen = dihydrotestosterone
- In some tissues: testosterone
is converted to
estradiol by P450 aromatase, e.g.:
- fat
- liver
- hypothalamus (possible role in a
gonadal function regulation)
- Testosterone
Degradation:
- production of
inactive agents (androsterone
& etiocholanolone)
- subsequent
conjugation
- urinary excretion
- Adrenal
Products:
- androstenedione
- dehydroepiandrosterone (DHEA)
- dehydroepiandrosterone sulfate
(DHEAS)
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| testosterone
propionate |
testosterone
enanthate |
testosterone
cypionate |
Pharmacological Effects:testosterone
& derivatives
- Mechanisms of Action: testosterone
& derivatives
- Testosterone:
Intracellular target sites
- Converted to 5a dihydrotestosterone (primary
androgen) by 5-a
reductase in certain tissues:
- skin
- seminal vesicles
- epididymis
- prostate
- Testosterone/dihydrotestosterone:
- bind to cytosolic
androgen receptor
- subsequent process
is similar to that determined for estradiol/progesterone
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- Effects: androgens
- Puberty:
male --
- secondary sex
characteristics
- androgen + inhibin result in gonadotropic
secretion suppression
- Women: androgens produce
physiological changes similar to those
observed in the male: (e.g., facial/body
hair growth; clitoris enlargement;
frontal baldness; more prominent
musculature)
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Clinical Uses
- Androgen replacement treatment -- Men:
- hypogonadal men: androgen
replacement/augmentation
- pituitary deficiency:
androgen is used --usually not
gonadotropin
- androgen
added at puberty to promote
growth spurt/secondary sex
characteristic development
- long-acting agent is used:
- testosterone
enanthate
- testosterone
cypionate
- Other
agents/routes of administration:
- testosterone
propionate -- duration of
action is too short
- transdermal:
- testosterone
-- scrotal application
(and others areas)
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- Gynecological Disorders:androgens
- Used with caution
due to undesirable side effects
- Androgens:
- reduce
breast engorgement during
postpartum (usually with
estrogens)
- treat
endometriosis (danazol -- weak
androgen)
- In
combination with estrogens:
postmenopausal replacement
therapy to reduce endometrial
bleeding {associated with
estrogen monotherapy}
- chemotherapy: premenopausal women
with breast tumors
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- Protein Anabolic Agents:androgens
- Androgen/Anabolic steroids
+ diet + exercise reverse ® protein loss after:
- trauma
- prolonged
immobilization
- individuals with
debilitating illness
- trauma
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- Anemia:androgens
--
- Recombinant
erythropoietin: has now replaced
androgens for treatment of:
- aplastic anemia
- Fanconi's anemia
- sickle cell anemia
- hemolytic anemias
- myelofibrosis
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- Growth Stimulation:androgens
- Effective in stimulating
growth in boys, with delayed puberty
- Proper use ® normal
height
- radiological evaluation of
epiphyses may help control therapy (note:
hormonal action at epiphysial regions
persist after therapy is stopped)
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Adverse Effects:androgens
- Masculinizing
actions
- women/prepubertal children
- Effects of women --
testosterone:
- hirsuitism, acne,
depression of menses, clitoral
enlargement, voice deepening,
endometrial bleeding
(progestational effects), serum
lipid alterations.
- Androgens
should not be used in children:
- may cause detrimental
changes in maturation of CNS centers
involved in sexual development; also
peripheral effects on external genitalia.
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- Synthetic Androgens/Anabolic Substances
-- 17-alkyl-substituted
steroids
- Hepatic dysfunction --
- increased
sulfobromophthalein retention
- increased AST
levels (aspartate aminotransferase)
- clinical jaundice
may appear (cholestatic jaundice
reversible)
- older males:prostatic
hyperplasia
- Replacement therapy in men:
- acne, sleep apnea,
phases permit, gynecomastia, erythrocytosis.
- supraphysiologic
doses: azoospermia, acting,
reduced testicular size --long
recovery time
- high-dose alkylated androgens:
- peliosis
hepatica
- cholestasis
- hepatic
failure
- reduce
plasma HDL2
and increase LDL
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Contraindications: Androgenic Steroids
- pregnant women or women who may become
pregnant during therapy
- children
- Men with breast/prostatic carcinoma
- patients with renal/cardiac disease in
which edema development could worsen the
underlying disease state
- possible relationship between treatment
of aplastic anemia with androgen anabolic agents
and development of hepatocellular carcinoma.
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Androgen Suppression & Antiandrogens
- Androgen
Suppression:
- Management of advanced prostatic
carcinoma:
- Orchiectomy--
undesirable option
- large dose
estrogen (to reduce androgen
availability)-- undesirable
option
- Gonadotropin-releasing
hormone analogs also work, e.g.:
- Leuprolide
acetate: gonadotropin
releasing hormone analog
- produce
gonadal suppression with
constant blood level (not
pulses)
- subcutaneous--
daily or depot injection
- effective
in management of
prostatic carcinoma
- Goserelin:once per month
-- subcutaneous
slow-release formulation
- Testosterone
levels fall to 10% of the initial
values (after a significant
initial increase, during which
time tumor activity/symptoms may
also increase)
- This
initial stimulation may be
suppressed by combining the GnRH
agonist with flutamide
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