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HORMONES: STEROIDS Previous hormones: the prostaglandins and adrenalin. Insulin (a 51 amino acid protein) is another.

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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HORMONES: STEROIDS Previous hormones: the prostaglandins and adrenalin. Insulin (a 51 amino acid protein) is another.

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  1. 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.

  2. 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

  3. 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)

  4. 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

  5. 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

  6. 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)

  7. 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

  8. 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)

  9. 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

  10. 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

  11. 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)

  12. 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))

  13. 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)

  14. 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/

  15. 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)

  16. 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%)

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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)

  22. 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

  23. 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.

  24. 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.

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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]

  30. 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’

  31. cGMP = cyclic guanosine monophosphate GTP = guanosine triphosphate NANC = nonadrenergic-noncholinergic neurons NO = nitric oxide PDE5 = phosphodiesterase type 5 (from: www.viagra.com)

  32. 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$!

  33. 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

  34. 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)

  35. 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

  36. 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)

  37. 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?

  38. 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

  39. 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

  40. 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)

  41. Dexamethasone (Dexasone) is 25x more potent still, dose 0.5 mg

  42. 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!

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