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DrWelch txs low T if pt has sx and levels below 3000


TESTOSTERONE
androgenic and anabolic effects
men make 40x more than women
women's receptors hold onto the T harder
anabolic effects: protein metab, development and preservation of muscle, bone mass & strength
also increases EPO-->RBC production
mainly produced by Leydig cells in testes
also in ovaries and by zona reticularis of adrenals
T and its metabolites bind to specific nuclear receptors-->changes gene transcription

ENZYMES that metabolize T
5 alpha reductase
aromatase
both part of the P450 system

5 ALPHA REDUCTASE
T metabolized/activated to DHT by 5-alpha reductase enzyme
T or DHT may be inactivated and cleared by enzymes that hydroxylate at 6, 7, 15, 16 positions
inhibitors: saw palmetto, finasteride/proscar

AROMATASE
T metabolized to Est by aromatase enzyme
aromatase is CPY19A1
once T is converted to Est (via aromatase) it doesn't turn back to T
bodybuilders get "moobs" dt aromatase action
inhibitors used off label by body builders who are taking anabolic steroids
inhibitors also used to tx breast & ov CA in postmenopausal women: keep est down
mb used to stim ovulation, or for endometriosis
also used to limit age-related decline in T
inhibitors: white mushrooms, nonselective: Aminoglutethimide, Testolactone, Selective: Anastrozole, Letrozole, Exemestane, Vorozole, Formestane, Fadrozole

HIGH DIHYDROTESTOSTERONE
-->alopecia: male pattern baldness
-->prostatic hyperplasia

ANDROGEN EFFECTS

FETAL DEVELOPMENT
at first gonads can become either testes or ovaries
androgens cause masculization of developing male fetus
at 4 weeks gestation the choice is made hormonally
dt SRY sex determining region of Y chromosome
T-->development of male genitalia
or androgen insensitivity syndrome (AIS) can cause XY individual to develop like a female

SRY region linked to fact that men get more dopamine-related diseases
ie schizophrenia, Parkinson's disease
SRY makes a protein that controls dopamine concentrations

Wolffian ducts develop into the epididymis, vas deferens and seminal vesicles
action of androgens supported by hormone from Sertoli cells known as MIH
MIH = Mullerian Inhibitory Hormone
MIH keeps Mullerian ducts from developing into fallopian tubes etc

embryo starts making LH around week 11-12 ??? or starts making HCG?
HCG promotes differentiateion of Leydig cells and their androgen prodcution
androgen action in target tissues involves conversion of T-->DHT

PUBERTY
in puberty big increase-->incr size of penis and testes, forehead and jaw
secondary sexual characteristics
exogenous T during puberty causes early closure of the epiphyseal bone plates-->endodermic build
-->short, stocky, muscular

bones and brain are two tissues where primary effect of T is by way of aromatization to E2
in bones E2 accelerates maturation and epiphyseal plate closure
in CNS E2 is most imp feedback to hypothalamus, influencing LH secretion

TESTOSTERONE IN ADULTS
-->sperm production, fertility, libido
-->bone and muscle maintenance
sertoli cells need paracrine androgen signal to make sperm

ANDROGENS AND THE BRAIN
circulating androgens influence human behavior
some neurons sensitive to steroids
implicated in aggression and libido
androgens can alter the structure of the brain in mice, rates, primates, producing gender diff
numerous reports support this
Zuloaga 2008 in Hormones and Behavior

BRAIN DIMORPHISM
several brain areas are sexually dimorphic
Sexually Dimorphic Nucleus of the PreOptic Area (SDN-POA) is sev times larger in males
female rats pre- and postnatally exposed to T or to synthetic EST, SDN-POA appeared sim in size
to what????

DIMORPHISM AND TRANSSEXUALITY
Interstitial Nucleus of the Anterior Hypothalamus (INAH-3) is 3x bigger in males
Bed Nucleus of the Stria Terminalis (BNST) is 2.5x larger in men
part of the BNST, the posteriomedial bed nucleus (BDSTpd)
is female sized in male to female transsexuals
in female to male trans the # of somatostatin neurons in the BNSTpd was in the normal male range

FALLING IN LOVE and PARENTING influence levels
decreases's men's T levels
increases women's T levels
(Marazziti, Canale, 2004, in Psychoneuroendocrinology)
-->temporary reduction in differences between the genders-->easier match???
fatherhood also decreases T levels in men-->better paternal care??
(Berg, Wynne-Edwards, 2001, Mayo Clinic)
motherhood-->incr T: to fight off the tiger??
**this brings up a question: if a pregnant woman is not in love, is her child more masculine?
**fodder for my theories about homosexuality

INDICATIONS FOR EXOGENOUS T ADMINISTRATION
generally exogenous has equal androgenic and anabolic effects
prepubertal boys with pituitary dwarfism
postpubertal hypogonadism, inadequate T production, infertility, ED, low libido,
loss of muscle mass and tone, incr osteoporosis, loss of axillary or pubic hair
refractory anemia, bone marrow suppression
kidney disease (low EPO)
severe osteoporosis
transsexual female-->male
not approved but used by body builders, athletes to incr lean body mass, muscle, aggressiveness
anti-aging

ROUTES OF ADMINISTRATION
most used: gel or patch topical or IM
transdermal: skin patches, creams, gels
gels and patches dosed daily
oral ineffective dt 1st pass metabolism, but sublingual seems to work
older po preparations-->incr liver dz incl hepatitis, carcinoma
injectable: IM (T cyprionate is ester form w/ salt and oil, T enanthate in oil)
dosing for injx is ev 2 wks, or one with lower dose for less peaks/troughs
oral, buccal, sub-linqual lozenges

ADVERSE EFFECTS
elevated LDL, decreased HDL-->incr risk of atherosclerosis and CAD
fluid retention and edema
incr RBC mass-->polycythemia vera-->incr blood viscousity-->ischemia
incr TXA2-->incr clotting
exacerbation of sleep apnea (what's the mechanism for this?)

SE in MALES
in spite of this list T replacement in men has a good safety record
acne, oily skin
baldness
gynecomastia
priapism
incr risk of BPH, prostate CA
reduced sperm count and infertility dt neg feedback

SE in FEMALES
exogenous T in females not often used dt incr risk of breast CA
virilization
hirsutism
acne
deepening of voice
clitoral enlargment
menstrual irregularities

SE in CHILDREN
abnormal rate of sexual maturation
diminished height dt premature growth plate closure

??? what about effects of maternal T on fetus?
my curiousity: how much does sexual preference depend on hormones in this stage?

in ATHLETES
liver abnormalities
gynecomastia, breast cysts
cystic acne
premature epiphyseal plate closure
increased aggression ("roid rage")

OTHER ANDROGENS
(besides testosterone)

DHEA: dehydroepiandrosterone, produced in adrenal cortex from cholesterole, primary precursor of natural estrogens, also called dehydroisoandrosterone, or dehydroandrosterone

ANDROSTENEDIONE (Andro): androgenic steroid produced by testes, adrenal cortex and ovaries. Mb converted to T or other androgens or estrone. Use for body building banned by IOC et al.

ANDROSTENEDIOL: the steroid metabolite thought to be main regulator of gonadotropin secretion.

DHT: dihydrotestosterone, a metabolite of T and 5x more potent androgen than T because it binds more strongly to androgen receptors and can enter the cell's nucleus and bind directly to the DNA. Areas of binding are called HREs, hormone response elements, influences gene trasncription with androgenic effecs. If there is a 5-alpha reductase deficiency a fetus will continue developing into a female with testicles.??? Produced in adrenal cortex??? I was under the impression that T could be converted to DHT at the tissues. DHT is an estrogen agonist so meds that reduce DHT may cause gynecomastia.


ANABOLIC STEROIDS
AAS = anabolic-androgenic steroids
synthetic derivatives of T with more anabolic than androgenic effect
incr protein synthesis
approved uses: refractory anemia, severe osteoporosis,
severe wasting conditions such as AIDS and cancer
muscle building effect-->widespread abuse
SE: incr LDL, decr HDL, acne, HTN, liver damage


ANTI-ANDROGEN TREATMENT
used for tx of advanced prostatic cancer
normal growth of prost tissue reg by T and DHT
may achieve tumor regression
only palliative, not a cure
Leuprolide/Lupron

***********************************************************

TESTOSTERONE CYPIONATE
You think I'm testy now, just wait til I get my shot.
made from wild yam, ester form in an IM shot to glu
class: androgenic hormone
indications: T replacement
MOA: changes gene transcription
char: IM, patch, gel, SL lozenges
(patch applied to scrotum after shaving, skin gets sensitive to adhesive)
dosed daily for patches or gel, 1-2 weekly for injection
SE: incr LDL/HDL, CAD, edema, PCV, incr TXA2, sleep apnea worse, acne, baldness, gynecomastia
priapism, incr BPH and prost CA, reduced sperm count, virilization of female, clitoral enlargment,
menstrual irregularities


LEUPROLIDE/LUPRON
This drug threw my sex hormones for a leup.
class: anti-androgenic and anti-estrogenic hormone
indic: prostate CA, precocious puberty, endometriosis, uterine fibroids
part of some protocols of IVF (recruit multiple follicles, prevent premature ovulation)
MOA: synthetic analog of gonadotropin releasing hormone (GnRH)
reduces testosterone and estrogen levels
GnRH analog-->decr T and est-->incr FSH, LH
char: SQ, IM. preparations have different t1/2s
SE: decr libido, impotence, nausea, vomiting, hot flashes,
night sweats, arthralgias, myalgias, osteoporosis
DrM does NOT use this drug

FINASTERIDE/PROSCAR
I can pee just FINa but I can't donate blood.
very popular drug
class: anti-androgen
indic: BPH, low dose (1mg) for male pattern baldness, high dose for prostate CA
48% of men taking propecia (finasterid 1mg) regrew hair, 42% had no more hair loss
must keep taking it to keep hair, works best in crown area

MOA: 5-alpha reductase inhibitor-->limits conversion of T to DHT
char: po qd for men only, wash your hands after dosing
CI: can't donate blood
CI: women who are or may become pregnant should not handle the product dt risk of birth defects
SE: decr libido, ED, impotency, depression, gynecomastia, breast swelling/tenderness

ALPHA BLOCKERS
I'm an aging alpha male and I can pee no prob.
drugs: Doxazosin/cardura, Terazosin/hytin, Tamsulosin/flomax, urimax, Silodosin/ureif
(tamulosin contains a sulfa moiety, beware sulfa allergies)
class: anti-andrenergic
indic: BPH, part of initial therapy along with a 5 alpha reducstase inhibitor
MOA: antagonizes alpha 1 andrenergic receptors-->relaxes smooth muscle in vasc of prostate and bladder neck-->decreased resistance to urine flow
char:
SE: weakness, orthostatic hypotension, nasal congestion

SILDENAFIL CITRATE/VIAGRA
Hey baby how do you like the results of my increased cGMP? A little headache won't stop me.
class: phosphodiesterase type 5 inhibitor (PDE5I)
indic: BPH, pulmonary hypertension
MOA: cGMP not broken down-->incr cGMP-->relaxation of smooth mm around BVs-->penis fills with blood
char: take 30mins-4 hours before sex, 25, 50 and 100mg tabs available but DrM says dose is 25mg
take no more than 1 tab/day
char: dose for pulm HTN: one 20mg tab tid, 20mg dose marketed as Revatio
SE: mc: headache, sinus/nasal congestion, flushing, dyspepsia
SE: vision changes, photophobia, cyanopia (see blue)
SE: priapism, ventricular arrhythmias, stroke, MI
CI: liver, kidney failure, recent MI, low BP
CI: don't mix with nitrates, could cause BP crash
CI: hereditary retinal degeneration disorders dt risk of incr intraocular pressure and acute closed angle glaucoma
(other drugs with same mechanism: Tadalafil/cialis, Vardenafil/levitra)

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