Transcript 8 Steroids

HORMONES: STEROIDS
Previous hormones: the prostaglandins and adrenalin.
Insulin (a 51 amino acid protein) is another.
A wide group of hormones contain the steroid structure.
18 20
21
12
1
2
3
5
13
H
9
14
10 H 8 H 15
4 H 6
18
17
16
11
19
19
1
3
7
numbering
shape
11
17
Steroid sources:
HO
Cholesterol
[from animals]
liver uses as source
O
O
O
O
OH
OH
HO
Glu - Gal - O
Diosgenin (yams) Digitalis (fox glove)
[from plants]
Drug companies use as source
Cholesterol found in all animals –
liver converts to other steroids and can synthesize it if not
enough (~200mg) in diet
Isolated 1812 - structure determined 1932
Natural Sex Hormones:
T
OH
O
T = 17b-hydroxyandrost-4-en-3-one
P = pregn-4-ene-3,20-dione
E = estra-1,3,5(10)-triene-3,17b-diol
P
COCH3
O
Male
[androgen]
Testosterone
E
Androstane
Pregnane
Estrane
OH
O
HO
Female
[gestogen]
Progesterone
Female
[estrogen]
Estradiol
[Estrone]
Secreted by testes
ovaries
ovaries
Controls 2o sex characs
(hair, voice, muscles, etc)
Prepares uterus for
pregnancy
Controls 2o sex chs
(breasts, hair, menstrual
cycle)
FEMALE CYCLE:
1)
PITUITARY gland releases follicle stimulating hormone (FSH)
which causes the follicle to develop in to an immature egg.
As the follicle develops, it releases ESTROGENS, which
SHUT OFF FSH production so that only one egg develops at
a time. These also cause expansion of the uterus lining.
2)
ca. Day 14: ovulation occurs as egg leaves follicle –
ESTROGEN production SHUT OFF but PROGESTERONE
production STARTS
PROGESTERONE: keeps FSH shut off, keeps uterus
developing, inhibits uterine contractions and enlarges breasts
3)
IF egg fertilized: P produced throughout pregnancy
IF egg NOT fertilized: P shuts off, FSH production begins,
uterus shrinks, egg flushed from body at ca. Day 28
Early in cycle: ESTROGENS present
Later in cycle: PROGESTINS present
So if we were to supply P or E:
FSH stays shut off = no eggs = no pregnancy
However both are metabolised, so would need to inject
Oral Substitutes: ‘The Pill’ > $3 B/y
To make a pill we need:
an active compound that could be oral and a cheap source
History:
O
OH
COCH3
O
HO
O
Ethisterone
Diosgenin
O
19-norprogesterone
1934 H.H. Inhoffen: made Ethisterone as an oral progesterone
substitute, but dose needed was large and no good source of
material (1940: progesterone was $200/g)
1944 Russel Marker (Penn. State) establishes SYNTEX and
finds a route to convert DIOSGENIN (from Mexican yams) to
progesterone. Reduced progesterone to 20c/gram (current)
O
OH
COCH3
O
O
19-norprogesterone
HO
O
Ethisterone
Diosgenin
1951: Carl Djerassi makes 19-norprogesterone;
4-8 x more potent than progesterone
1956: Syntex (cheap source) combines Djerassi and Inhoffen’s
results to make Norethindrone (left)
OH
OH
Searle makes isomeric
Norethynodrel (right)
O
1956-59 Pills are tested in S America
O
1960: the pill is released in N America and Europe
SEARLE: ENOVID
Norethynodrel + Mestranol
ORTHO: ORTHONOVUM Norlutin + Mestranol
SYNTEX: NORINYL
Norlutin + Mestranol
The ingredients: Progestins (progesterone substitutes)
OH
O
Norethindrone
(Norlutin)
OH
OH
O
O
Norethynodrel
Norgestrel
(levonorgestrel)
(more recent variety)
Estrogen substitutes
OH
HO
Ethynylestradiol
OH
CH3O
Mestranol
In 1960: pills used 10mg progestin + 0.15mg estrogen
By 1970: 1mg progestin + 0.1 mg estrogen
Today: even less estrogen
Ortho 10/11 uses:
0.5 mg norethindrone and
0.035mg mestranol for first 10 days,
WHITE
1.0 mg norethindrone and
0.035mg mestranol for next 11 days,
PEACH
Nothing for last 7 days GREEN
The estrogen prevents spotting
(bleeding)
The blank week allows a normal
period to occur
Ortho 7/7/7 is now
more common, uses
norethindrone and
ethynylestradiol
$72/3month
0.5, 0.75 and 1mg of the progestin (norethindrone) each with
35mg of the estrogen (ethynylestradiol) + 7 blanks (green)
There are many
manufacturers
and many varieties:
those with 21 active
pills allow period,
blank pills always
different color
If you take 28 active
pills – no period
Also note: there are
equivalent ‘Patch’
systems that slowly
leak the same drugs
(eg. EVRA (Ortho))
Longer term solutions:
Seasonale
(Dura-Med/Barr USA)(Palladin CAN)
91 day regime, 84 active pills = one period every 3 months
Approved US (2003) and Canada (2007)
Levonorgestrel (150mg) + ethynylestradiol (30mg)
Alesse (Wyerth)
Even lower dosage of estrogen (20mg):
21 (pink) or 28 day (pink, green) regime
Levonorgestrel (100mg) + ethynylestradiol (20mg)
LYBREL approved June 2006 by FDA
90 mg levonorgestrel, 20 mg ethynyl estradiol
Continuous use – no periods at all, though ~ 40%
find some spotting during first year
WYETH REPORTS THAT
The study showed that 99 percent of 187 participants experienced either a return to menses
or became pregnant within 90 days after stopping the study drug. Investigators reported that
four women became pregnant before returning to menses and two women reported a return
to menses more than 90 days after the completion of the study.
Brings up the question: How to recognize if you are pregnant, while using? – Test
Will be sold as Anya in Canada – but still not approved?
http://www.lybrel.com/
DIANE-35 (Berlex Canada) (Schering US) $70/3 month
Side effects of birth control pills:
better hormone level control, acne is cleared up
Diane-35 is specifically for severe acne control and excess
body hair (it is an anti-androgen)
O
OH
Studies indicate 4x increase in stroke risk
It contains cyptoterone acetate (2mg)
(blocks androgen receptors)
and ethynyl estradiol (35mg)
O
Cl
cyproterone
MINIPILLS (No Estrogen): Low dose of progestin every day
egs. ‘Micronor’ (Ortho) and ‘Ovrette’ (Wyeth)
Ovulation normal: cervix secretes glue
that prevents passage of sperm, and
uterus is more hostile to implantation of
an egg
No estrogen = less risk of blood clot
3x risk of pregnancy over combination
pills (actual risk about 3%)
Long life injection - Depo-provera – (Pfizer)
medroxyprogesterone acetate
More soluble in fat: slowly leached out
150 mg injected every 3 months ($48)
COCH3
OCOCH3
O
If within 5 days of period, effective
immediately
Success rate 99.7%
NOV 2004: Health-Canada and FDA alerts
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/depo-provera_hpc_e.html
http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html
Warn about possible bone density loss (~3% in hip/y, 6% over 2 yrs)
with prolonged use – seems to recover after stopping drug
IUD’s Intra uterine devices
Progestasert
(a plastic T), leaks progesterone daily, lasts about 1 yr
same problems of all IUD’s, see later
Mirena (Berlex): Plastic IUD with 52 mg of levonorgestrel
leaks 20mg/day, >99% effective, lasts about 5 years
Nuvaring (Organon): Approved 2004 (Canada) flexible transparent ring
uses etonorgestrel (an 11-exomethylene norgestrel derivative) + ethynyl
estradiol, so leaks P + E directly into the uterus
Copper IUD’s
egs. Nova-T and Gyne-T
Not much used in Canada:
Problems: blood infections caused by irritation/perforation of uterus
Copper inhibits egg implantation
Many lawsuits in 70's and 80's over the copper-7 and the Dalcon
shield (~10M total users) - perforations followed by infections.
For interesting account see:
http://www.manhattan-institute.org/html/cjm_36.htm
OH
MORNING AFTER PILLS
HO
DES
Until 1980 UVIC health services used
DES (diethylstilbestrol, 25 mg)
Originally DES used in 40-50's to prevent miscarriages, but 15 years
later, vaginal cancer in daughters observed, so this use stopped
Also used as cattle growth hormone (20% gain) - banned in 1973
As an abortant: no offspring to get cancer, but unpleasant drug
to take
NOW
4 OVRAL TABLETS (white not pink)
(each has 500mg of norgestrel (±) and 50mg of ethynylestradiol)
take 2 + 2 12 hrs later within 3 days of intercourse, > 98% effective
PLAN B (Paladin labs, Barr Labs (Can))
2 tabs, 750mg each
levonorgestrel, taken within 12 hours of each other
OTC in Canada (as of June 06)
CONTRACEPTIVE SPONGES
Today® Sponge (see Seinfeld episode!)
reserve for 1,000 mg of nonoxynol-9, an effective spermicidal agent
that is continuously released into the vagina in small amounts through
a 24-hour wear time
Polyurethane foam traps and absorbs semen before sperm have a
chance to enter the cervix: NOT VERY EFFECTIVE (84-87%)
No protection against HIV/STD warning
Spermicide used on sponges is Nonoxynol-9:
C9H19
(OCH2CH2O)nOH
a non-ionic detergent used in shampoos
ABORTION PILL - RU-486
(Roussel-Uclaf, France)
MIFEPREX (2000 in US)
Me2N
OH
Invented as cortisone antagonist,
but progesterone antagonist as well
Approved for termination during
first 49 days (63 d from last period)
O
Use 600mg (3 x 200mg), then oral prostaglandin (misoprostol) 48h
later to induce contractions – abortion occurs within 4-22 h
96% success - must have surgical if fails.
Side effects:
bleeding for ~9 days
blood transfusion in 0.1% cases
heart attack 0.02%
however surgical abortion has risks at least as great or greater
Over last decade, >2M RU-486 abortions worldwide in 29 countries:
>465,000 in US since 2000 – 4 deaths (from vaginal infection)
However, see also warnings at:
http://www.fda.gov/cder/drug/infopage/mifepristone/default.htm
Not approved in Canada: one woman died in trial which was halted
Distributed by Danko Labs (NY), made in China.
RELATIVE EFFECTIVENESS OF VARIOUS METHODS
(Average % PREGNANT DURING ONE YEAR OF USE)
BEST TYPICAL
MALE VASECTOMY
FEMALE TUBES TIED
NORGESTREL INSERTS
DEPO OR PATCH
ORAL COMB PILLS
MINI PILLS
COPPER IUD
PROGESTIN IUD
MALE CONDOM
WITHDRAWAL
DIAPHRAGM
SPERMICIDAL SPONGE
RHYTHM/TIMING
NONE
0.1%
0.2%
0.2%
0.3%
0.5%
1.5%
0.8%
2%
2%
4%
6%
6-9%
9%
85%
0.15%
0.4%
0.2-0.4%
0.3%
3%
3%
3%
3%
15%
18%
18%
18-28%
23%
85%
PREGS/MIL
1,250
3,000
3,000
3,000
12,000
20,000
20,000
25,000
75,000
110,000
120,000
170,000
170,000
850,000
Male Contraceptives:
sperm take 3 months to make; about 108 released per day
Injected testosterone (and anabolic steroids) reduce sperm:
probably shut down synthesis in testes
many undesirable side effects
Progestins and estrogens also reduce sperm production:
reduce sexual interest
can lead to loss of bone and muscle mass
CHO OH
CHINA (1970-80, >10,000 subjects):
HO
OH CHO
OH
HO
OH
GOSSYPOL: seed of cotton plant
daily oral pill gave low sperm count
reversible in 3 months
no reduction of performance, oral, cheap
BUT Side Effects: nausea, inability to sweat,
takes 3 months to lower sperm levels, long term use
causes sterility
India (2002):
RISUG (Reversible Inhibition of Sperm Under Guidance)
Uses a polymer injected (or implanted) into vas deferens
(sperm tube):
effective for 5-10 years
removable by sodium bicarbonate wash
N. American trials since 2006 – not on sale yet?
http://www.medicalnewstoday.com/medicalnews.php?newsid=40720
IMPOTENCE DRUGS - VIAGRA
~ 20-30M NA men suffer some kind of erectile disfunction
How it is supposed to work:
Muscles in the penis keep the artery walls contracted, restricting
blood flow
To get an erection: during stimulation, nerves release NO which
binds to the enzyme guanylate cyclase turning on synthesis of
cyclic-GMP from GTP (guanosine triphosphate).
c-GMP causes Ca2+ ions to flow OUT of the penis muscles which
then relax allowing blood flow in causing an erection
[c-AMP does same thing in the heart]
NH 2
N
N
O
HO P O
OH
Base'
Base'
O
O
HO
OH OH
N
N
O
P O
OH
O
N
OH
Guanine
H2N
AMP/GMP
Adenine
c-AMP/c-GMP
N
At the end of the process, c-AMP and c-GMP are broken
down by enzymes called PHOSPHODIESTERASES, PDE’s,
muscles start contracting, erection dies
Inhibition of these enzymes would keep c-AMP/c-GMP
around longer so a longer erection:
Viagra inhibits PDE-5 (penis)
For comparison:
Caffeine inhibits PDE-3 that breaks down c-AMP and so
raises c-AMP levels:
change in the flow of Ca2+ ions out of heart muscles (like
adrenaline) causes ‘heart pounding’
cGMP = cyclic guanosine monophosphate
GTP = guanosine triphosphate
NANC = nonadrenergic-noncholinergic neurons
NO = nitric oxide
PDE5 = phosphodiesterase type 5
(from: www.viagra.com)
O
N
N
EtO HN
N
O2S
O
EtO HN
N
Pr
O2S
N
N
sildenafil
N
N
O
H
N
Pr
O
NH
O
N
N
vardenafil
O
tadalafil
VIAGRA (sildenafil) Pfizer: 50 or 100 mg blue pills
Onset ca. 20 mins to 1 h, lasts 4h (about 70% success rate)
Side effects: blue-green haze (poor PDE-5/PDE-6 selectivity)
Launched in March ‘98, by July ’98: 16 deaths
Not recommended for cardiac patients! 1999 sales: 1.22B$!
O
N
N
EtO HN
N
O2S
O
EtO HN
N
Pr
O2S
N
sildenafil
N
N
Pr
O
NH
O
N
N
N
O
H
N
vardenafil
O
tadalafil
Newer Versions
CIALIS (tadalafil) Lilly
works faster, lasts longer (24-36h)
10 and 20 mg, orange-yellow
less blue-green vision
LEVITRA (vardenafil) Bayer/GlaxoSmithKline
orange, 10, 20 mg
ANABOLIC STEROIDS ($1.4B est /y in USA):
Steroids that build tissue (muscle mass) by increasing
protein synthesis; also have androgenic properties (male
OH
sexual characteristics)
eg. Testosterone:
O
builds muscles
excess shuts of FSH (decreases sperm production in
males) leading to long term sterility, testicular atrophy
acne, baldness
For women: facial hair, baldness, voice deepening
irreversible menstrual cycle changes
For youth:
premature halting of growth (height)
The liver oxidizes testosterone, so most on market are MORE
FAT SOLUBLE (also more toxic to liver in general)
OH
OH
O
HN
N
H
Stanazolol
[Ben Johnson]
O
Androstenedione
[Mark McGuire]
O
H
Primobolan
[Alex Rodriguez]
Johnson lost 100m gold 1988 Seoul Olympics
stanazolol was a vet steroid, used to fatten cattle
McGuire broke home run record for St Louis Cardinals
admitted to taking adrostenedione, not then banned by baseball
Rodriguez admits Feb ’09 to using Primobolan in 2003
Other ‘designer’ steroids:
OH
O
Nandrolone
O
OH
OH
OH
O
O
THG=tetrahydrogestrinone
[Barnes, Vezina] [Chambers, Toth]
Gestrinone
Trenbolone
Nandrolone:
Barnes (‘96 Olympic shotput champ)
now has lifetime ban after 2nd test in ‘98
Vezina cost Canada a gold in ‘99 Pan-Am
Games roller hockey
IOC limit = 2 ng/mL(men) and 5 ng/mL (women)
for Nandrolone in urine (women are higher because produced as a
metabolite from estrogens)
THG: June 2003 US Track championships:
coach tipped the anti-doping agency about a new steroid
(supplied a syringe - made identification easier)
Used LC-MS to test for THG
Change in rules: samples now stored for future testing as new
drugs are identified
Beijing Olympics 2008: >5000 drug tests, 9 positives
Athens Olympics 2004: >3000 drug tests, 24 positives
Is drug use on the decline…or are the athletes a step ahead?
Benzothiazepines:
O
O
N
S
S107
O
N
N
S
JTV519
Counteracts muscle fatigue by ‘stabilizing protein channels that
leak Ca2+ from muscle cells during strenuous exercise’
In development, but some indications this may have been
already used in Beijing (?)
Developers already have supplied WADA with a test that can
now detect this in 0.1 ng/mL in urine or blood
See: RSC Chemistry World Jan. 23, 2009
Corticosteroids: steroidal hormones secreted in the adrenal
cortex (immune and stress responses, inflammation, blood
electrolyte levels, etc.)
Cortisol (11-OH) and cortisone (11-one)
secreted daily (~ 25mg), most in morning, more if stressed
provides increased availability of energy from glucose, and
is the bodies most potent inflammation reducer
O
O
COCH2OH
OH
O
COCH2OH
OH
O
Cortisone
Prednisone (Deltasone)
Secreted by adrenal glands; oral pill as 5 mg dose or injected
Both reduce inflammation in doses > 25 mg/day:
treat hives
Allergies and asthma – fluticasone propionate (ADVAIR)
Use must be tailed down slowly
Very severe side effects of overuse
fat deposition (humps)
protein (muscle) wasting
Ca loss from bone (osteoporosis)
water retention (conserves Na+)
poor wound healing, ulcers,
glaucoma
Cushing’s syndrome is ‘natural’ excess cortisol production
(RU-486 used to treat)
Dexamethasone (Dexasone) is 25x more potent still,
dose 0.5 mg
PROSCAR (finasteride) Merck
Dihydrotestosterone (DHT) is
produced from testosterone by
a-reductase more as men age
DHT stimulates (benign) growth
of prostate – frequent urination
Proscar inhibits enzyme, about 50% of patents get shrinkage
and relief (~400,000 prostate surgeries per year)
At $1.40 per day = $1.5B per year!
Side effect of Proscar: reverses male pattern baldness!!
DANGER: pregnant women should not touch – deformation
of the fetus is known to result!