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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. Steroid sources:. Cholesterol Diosgenin (yams) Digitalis (fox glove) [from animals] [from plants]

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slide1

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.

slide2

Steroid sources:

CholesterolDiosgenin (yams) Digitalis (fox glove)

[from animals][from plants]

liver uses as sourceDrug 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

slide3

T = 17b-hydroxyandrost-4-en-3-one Androstane

P = pregn-4-ene-3,20-dione Pregnane

E = estra-1,3,5(10)-triene-3,17b-diol Estrane

Natural Sex Hormones:

T

P

E

MaleFemale Female

[androgen] [gestogen][estrogen]

TestosteroneProgesterone Estradiol [Estrone]

Secreted by testes ovaries ovaries

Controls 2o sex characs Prepares uterus for Controls 2o sex chs

(hair, voice, muscles, etc) pregnancy (breasts, hair, menstrual cycle)

slide4

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

slide5

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

slide6

History:

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)

slide7

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)

Searle makes isomeric

Norethynodrel (right)

1956-59 Pills are tested in S America

slide8

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)

Norethindrone Norethynodrel Norgestrel (Norlutin) (levonorgestrel)

(more recent variety)

slide9

Estrogen substitutes

Ethynylestradiol Mestranol

In 1960: pills used 10mg progestin + 0.15mg estrogen

By 1970: 1mg progestin + 0.1 mg estrogen

Today: even less estrogen

slide10

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

slide11

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)

slide12

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))

slide13

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)

slide14

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/

slide15

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 controland excess body hair (it is an anti-androgen)

Studies indicate 4x increase in stroke risk

It contains cyptoterone acetate (2mg)

(blocks androgen receptors)

and ethynyl estradiol (35mg)

slide16

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%)

slide17

Long life injection - Depo-provera – (Pfizer)

medroxyprogesterone acetate

More soluble in fat: slowly leached out

150 mg injected every 3 months ($48)

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

slide18

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

slide19

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

slide20

MORNING AFTER PILLS

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

slide21

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)

slide22

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:

a non-ionic detergent used in shampoos

slide23

ABORTION PILL - RU-486(Roussel-Uclaf, France)

MIFEPREX (2000 in US)

Invented as cortisone antagonist, but progesterone antagonist as well

Approved for termination during first 49 days (63 d from last period)

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.

slide24

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.

slide25

RELATIVE EFFECTIVENESS OF VARIOUS METHODS

(Average % PREGNANT DURING ONE YEAR OF USE)

BEST TYPICAL PREGS/MIL

MALE VASECTOMY 0.1% 0.15% 1,250

FEMALE TUBES TIED 0.2% 0.4% 3,000

NORGESTREL INSERTS 0.2% 0.2-0.4% 3,000

DEPO OR PATCH 0.3% 0.3% 3,000

ORAL COMB PILLS 0.5% 3% 12,000

MINI PILLS 1.5% 3% 20,000

COPPER IUD 0.8% 3% 20,000

PROGESTIN IUD 2% 3% 25,000

MALE CONDOM 2% 15% 75,000

WITHDRAWAL 4% 18% 110,000

DIAPHRAGM 6% 18% 120,000

SPERMICIDAL SPONGE 6-9% 18-28% 170,000

RHYTHM/TIMING 9% 23% 170,000

NONE 85% 85% 850,000

slide26

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

slide27

CHINA (1970-80, >10,000 subjects):

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

slide28

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

slide29

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]

slide31

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:

Caffeineinhibits 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’

slide32

cGMP = cyclic guanosine monophosphate

GTP = guanosine triphosphate

NANC = nonadrenergic-noncholinergic neurons

NO = nitric oxide

PDE5 = phosphodiesterase type 5

(from: www.viagra.com)

slide33

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$!

slide34

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

slide35

ANABOLIC STEROIDS ($1.4B est /y in USA):

Steroids that build tissue (muscle mass) by increasing protein synthesis; also have androgenic properties (male sexual characteristics)

eg. Testosterone:

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)

slide36

The liver oxidizes testosterone, so most on market are MORE FAT SOLUBLE (also more toxic to liver in general)

Stanazolol Androstenedione Primobolan

[Ben Johnson] [Mark McGuire] [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

slide37

Other ‘designer’ steroids:

NandroloneTHG=tetrahydro-GestrinoneTrenbolone

gestrinone

[Barnes, Vezina] [Chambers, Toth]

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)

slide38

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?

slide39
Benzothiazepines:

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

slide40

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

CortisonePrednisone (Deltasone)

Secreted by adrenal glands ; oral pill as 5 mg dose or injected

slide41

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)

slide43

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!