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Special Topic IV: Contraception

Special Topic IV: Contraception. By 2020, about 1.2 billion people, or 16% of the world’s population, will be entering their childbearing years. Holden C., (2002) Science 296:2172-3. HIV Infection Still on Rise.

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Special Topic IV: Contraception

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  1. Special Topic IV: Contraception

  2. By 2020, about 1.2 billion people, or 16% of the world’s population, will be entering their childbearing years. Holden C., (2002) Science 296:2172-3.

  3. HIV Infection Still on Rise • In 2002, an estimated 800,000 children aged 14 or younger became infected with HIV. Over 90% were babies born to HIV-positive women. • During 2002, ~ 5 million people became infected with HIV. The year also saw 3.1 million deaths • Sources: WHO; Holden C., Science 296, 2172-2173; 2002.

  4. Possible Solution Treatments combining a contraceptive with anti-STD treatment

  5. Intl. Congress on Gamete Biology: Emerging Concepts in Fertility and Contraceptive Development, New Delhi Feb. 22-25, 2006 • Organized by Drs. Koji Koyama & Satish Gupta, world leaders in development of ZP vaccine • In spite of 20 years of work, the contraceptive vaccine targeting the egg coat (ZP-vaccine) is not ready for human use

  6. (Long) History of Contraception

  7. Ancient Egypt & Middle East 3000 BC-AD 1100 • Spongy vaginal inserts to trap semen or to block cervix • Vaginal bung incorporating dung (symbol of decay) • Recipes described in the Kahun Papyrus suggest mixing crocodile dung with a paste of auynt (unidentified plant) • Also: mix of honey and natron (sodium carbonate) or auynt gum • Papyrus Ebers: A pad of lint soaked in a mixture of acacia tips and honey, used to block cervix (acacia tips can produce lactic acid, a common ingredient of modern day spermicides)

  8. Ancient Greece • Aristoteles 4th century BC: Olive oil • Plinius: encouraged abstinence • Dioscorides: inserting of black pepper after intercourse (also for sneezing); also formulated the concept of “safe period” (first 5 days after menarche) • Soranus of Ephesus 2nd century BC: cervical wool plugs impregnated with gummy substances (viscosity) or astringent solutions (cervix contraction); also recommended a thorough douche p.c.

  9. Medieval Asia China • Coitus reservatus (delay) • Coitus obstructus (pressure applied on urethra) Islamic World: • Avicena AD 1037: Pesaries • Ovaryectomy

  10. New World • Hopi: Jack-in-the-pulpit root powder • Shoshoni: Infusion of stone-seed* roots: Contraceptive properties confirmed by modern day lab experiments • Navaho: Infusion of rag-leaf bahia (claimed to make both sexes sterile) • Paraguay native tribes: Stevia rebaudiana* powder boiled in water Source: Bishop C. Sex & Spirit. Time-Life Books 1996; Tannahill R. Sex in History. Scarborough House Publishers 1992

  11. Europe • Coitus interruptus • Contraception seen as unnatural until late 19th century • Malthusian theory of population constantly outstripping resources; its advocates promoted contraception to limit overpopulation • Francis Place 1820s: sponge • Dr. George Drysdale, 1850’s: sponge & douche • Mid 19th century: improved condoms (vulcanization discovered 1843) • Friedrich Adolph Wilde, 1838: impression of cervix used to produce a rubber diaphragm

  12. The Pill • 1930s: Progesterone prevents ovulation in rabbits (Pincus & Chang) • Pill introduced to the public in the early 1960s • Synthetic hormones that mimic the way real estrogen and • progestin works in a woman's body • Margaret Sanger a lifelong advocate of women's rights and the use of birth control. In 1950, while in her 80s, Sanger underwrote the research necessary to create the first human birth control pill. Sanger raised $150,000 for the project. • Frank ColtonFrank Colton was the inventor of Enovid, the first oral contraceptive • Carl DjerassiCarl Djerassi was the inventor of modern oral contraceptives or the “pill”

  13. Contraceptives by Target Female Cs: Target ovum or ovary (active compound administered to female) Female Controlled Male Cs: Target male gametes in female reproductive system (administered to female) Male Cs: Target spermatogenesis by lowering androgen/estrogen levels or by interfering with spermatogenic cells in testis or epididymis

  14. Contraceptive Options Reversible: • Hormonal • Immunocontraceptives • Non-Hormonal Contraceptive Drugs • IUDs • Condoms • Spermicides Permanent: • Surgical Sterilization (vasectomy, tubal ligation) • Chemical sterilization (pets)

  15. Most Common Methods (USA) • Surgical sterilization (vasectomy & blockage of oviduct) • Oral/injectable contraceptives combined (estrogen/progestin pills/injectables), progestin-only contraceptives (NorrPlant implants, progestin-only injectable contraceptives, progestin-only mini-pills)

  16. Alternative Methods • Intrauterine devices (IUD; sperm immobilization, changes in the uterine lining; The Paragard IUD can remain in place for 10 years, while the Progestasert IUD must be replaced every year) • Barrier methods (male & female condoms, diaphragms) • Cervical cap (~48 h protection) • Spermicides (kill sperm; foam, cream, jelly, film, suppository, or tablet ) • Contraceptive sponge (contains spermicide nonoxynol-9; ~24 h protection) • Rhythm methods • Emergency contraceptives (morning after pill; delay ovulation or prevent implantation; no effect on implanted embryo) Source: U.S. Food & Drug Administration

  17. Contraceptive Market • Pharmaceutical Contraceptives in US, 2006: $2.2 billion (growth +8.7%) • Hormonal contraceptives loosing market share due to side effects and cancer risk • Combined contraceptives with added STD-control desired

  18. Problems with Hormonal Contraceptives • Unable to take pill on a daily basis (40%) • Weight gain • Mood changes • Breast tenderness • Headaches • Spotting or breakthrough bleeding • Increased STD (weakened immune response?)

  19. Contraceptive Controversy • Increased risk of breast, ovarian and other cancers, as well as strokes and myocardial infarction, thromboembolic disorders, cerebrovascular accidents, coronary artery disease, liver abnormalities, estrogen dependent cancers, and pregnancy. • Epidemiological studies do indicate a slight increase in low risk women and a significant increase in groups with one or more risk factors • (Reviews: Pymar and Crenin, 2000; Marsden, 2002).

  20. What Women Want: • User controlled contraceptive • Empowers them as decision makers • Added protection from STDs • 11% of women requested a pill with fewer side effects 30% asked for a pill that did not have to be taken daily

  21. A Perfect Contraceptive • Non-hormonal (no side effects like the pill) • Drug or vaccine • Contraceptive vaccine that would not affect ovarian function (current anti-ZP-immunocontraceptives do) • Reversible (immunity expires, drug can be discontinued) • Economical-cheap to produce & distribute • Targets unique to male/female gametes or reproductive tissues • Highly uniform batches (vaccine based on synthetic peptide/drug compound) • No need for regular daily/monthly dosage • Possibility of developing a contraceptive insert that could be combined with microbicidal/virucidal agents to reduce the transmission of STD, including HIV.

  22. The Female Contraceptive Targets • Oocyte within ovarian follicle • Ovulation • Ovulated oocyte • Sperm migrating to the site of fertilization in oviduct • Sperm binding to the egg

  23. ZP-Targeting Immunocontraceptives “Despite some promising advances, particularly in targeting the ZP proteins by female immuno-contraceptives, the promise of new contraceptive technologies remains largely unfulfilled.” • Immunization with purified oocyte zona protein ZP3 may result in ovarian damage and altered follicular growth, which translates into abnormal production of ovarian gonadotropins • Alternative routes of immunization are being explored (nasal mucosal immunization) • (review: Bradley and Bird, 2002). • (http://www.conrad.org the official web site of CONRAD Program for detailed information).

  24. Delivery Routes • Oral • Skin Patch • Subcutaneous Implant • Vaginal insert • Immunization (oral, nasal/mucosal, subcutaneous injection) • Synthetic delivery systems (immunostimulating complexes, microspheres, liposome emulsions)

  25. Mucosal Immunization • MI=the administration of a vaccine that enters body via mucosal membrane lining body cavities (gastrointestinal & urogenital tract, nasal passages) • Mucosal M-cells bring the immunogen from vaccine in contact with mucosal immune cells (lymphocytes); these lymphocytes produce antibodies (secretory IgA) • One mucosal immunization site can provoke antibody production in all other mucosal sites (IgAs travel in the body). Thus oral/nasal vaccines can stimulate vaginal/oviductal immunity • Currently approved mucosal vaccines: polio, cholera, typhoid fever • Under development: AIDS vaccine

  26. Making Needles Needless • Mucosal immunization prompts the immune system to produce two types of antibodies in different regions of the body: powerful IgA antibodies at mucosal surfaces, and IgG antibodies in the bloodstream • Injected vaccines trigger only IgG antibodies in the blood serum • By eliciting the immediate IgA response, mucosal vaccines protect the body against invading pathogens before they reach and damage internal organs • The protection of an IgG-inducing injected vaccine only kicks in after an infection starts • http://cache.technologyreview.com/BioTech/wtr_11747,259,p2.html

  27. Mucosal vs. Injectable Vaccine: • Easier to administer • No needle infection risk • Mucosa has the strongest immune system in the body; gut mucosa is the #1 largest immune organ in the body • Mucosal surface=400 square meters (skin surface=2 m2) • Strong, lasting protection • Better reversibility: Mucosal immunity fades more quickly than systemic immunity • BIG OPPORTUNITY: Contraceptive mucosal vaccine could be combined with mucosal STD vaccines (AIDS, chlamydia, herpes simplex, papilloma, gonorrhoea). STDs target reproductive tract mucosa, thus mucosal immunization would be more efficient than systemic one.

  28. WHO Research Priorities New Immunization Approaches: • Nucleic acid vaccines • Mucosal immunization: • to assess mucosal adjuvants: different routes and formulations, • to improve mucosal targeting of vaccines, • to improve nasal delivery for antigens; evaluation in human trials, and • to determine the impact on systemic immunity, including the induction of tolerance. • Vaccination in the neonatal period • Combined Vaccines: • http://www.who.int/vaccines-diseases/research/nva.shtml

  29. Recent Examples of Successful Mucosal Immunization in the Urogenital Tract MUCOSAL IMMUNIZATION WITH WHOLE-KILLED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) IMMUNOGEN (REMUNE) PLUS CgG ODN INCREASES IgA AND IMMUNE RESPONSES IN THE GENITAL TRACT Nancy Dumais1, Ronald B Moss2, Heather L Davis3, Kenneth L Rosenthal1 Conclusions: These results indicate that intranasal immunization with Remune plus immunostimulatory CpG ODN can induce potent immune responses in the murine genital tract. GENITAL CHALLENGE FOLLOWING MUCOSAL IMMUNIZATION WITH INACTIVATED gp-120-DEPLETED HIV (REMUNE) PLUS CpG ODN Nancy Dumais1, Janina Jiang1, Ronald B Moss2, Heather L Davis3, Kenneth L Rosenthal1 1Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario; 2Immune Response Corporation, Carlsbad, California; 3Coley Pharmaceutical Group, Ottawa, Ontario Nasal immunization with vaccine candidate prevents P. falciparum infection December 28th, 2005: Nasal immunization with a malaria transmission-blocking vaccine candidate, Pfs25, induces complete protective immunity in mice against field isolates of Plasmodium falciparum. Mucosal immunization with recombinant MOMP genetically linked with modified cholera toxin confers protection against Chlamydia trachomatis infection.Vaccine, 24(8): 1213-24. Chlamydia trachomatis is a major human health pathogen due to its role in sexually transmitted diseases. Thus, there is a need to develop an effective vaccine at the mucosal surface against this pathogen. In an effort to develop a mucosal vaccine, a modified cholera toxin gene was genetically linked to the C. trachomatis MoPn NiggII MOMP gene to generate a recombinant protein with the mucosal adjuvant properties of the cholera toxin and immunological antigenicity of the chlamydial protein.

  30. Male Contraceptives 1: Hormonal • Shuts down testosterone production by testis • Combination of progestin (blocks signals from pituitary to testis) & supplemental testosterone • Delivered through patch, implant or injection (oral delivery not effective) • Blood testosterone has to be replenished to avoid side effect (breast, lost sex drive, mood swings, aggressive behavior, prostate cancer) • Clinical trials in progress • Controversy: “chemical castration?”

  31. Male Contraceptives 2: Nonhormonal, Targeting Testis A. Blood-testis barrier: drugs to hold it open (premature release of spermatogonia), or to shut it down completely (no spermiation) • Pathway: cytokines controlling tight junctions in semin. tubules(Lui WY, et al., (2003) Transforming growth factor beta3 regulates the dynamics of Sertoli cell tight junctions via the p38 mitogen-activated protein kinase pathway. Biol Reprod. 68:1597-612. B. Miglustat, inhibitor glycolipid synthesis; treatment of Gaucher’s disease • Permits spermatocytes to cross blood-testis barrier, but alters spermatid elongation(van der Spoel AC, et al., (2002) Reversible infertility in male mice after oral administration of alkylated imino sugars: a nonhormonal approach to male contraception. Proc Natl Acad Sci U S A. 99:17173-8) C. Targets related to spermiation/sperm release into seminiferous tubule lumen • Integrins:Saito K, et al., Spermiation failure is a major contributor to early spermatogenic suppression caused by hormone withdrawal in adult rats. Endocrinology (2000) 141:2779-85. • Ionidamine (anti-cancer drug) disrupts integrins in semin. epithelium, causes premature spermiation(Siu and Cheng (2004) Dynamic cross-talk between cells and the extracellular matrix in the testis. Bioessays 26:978-92)

  32. Male Contraceptives 3: Non-Hormonal, Targeting Sperm in Epididymis & Beyond A.Disruption of epididymal fluid balance (e.g. c-Ros receptor KO model) B. Reversible Vasectomy-Reversible Inhibition of Sperm Under Guidance (RISUG), The De-Sperminator!!! • Injects a polymeric hydrogel into the vas to form a plug; plug dissolved with chemical reverser C. Sperm calcium ion channels/motility block • Ren D, et al., (2001) A sperm ion channel required for sperm motility and male fertility. Nature 413:603-9.

  33. Reversible Immunocontraception in Male Monkeys Immunized with Eppin M. G. O'Rand et al., 2004, Science 12 November 2004 Vol. 306. no. 5699, pp. 1189 – 1190: • Nine males immunized against Eppin, an epididymis-secreted sperm surface protein • Seven out of nine males (78%) developed high titers to Eppin, and all of these high-titer monkeys became infertile • Five out of seven (71%) high–anti-Eppin titer males recovered fertility when immunization was stopped • Effective and reversible male immunocontraception is an attainable goal • Devil is in details: Monkeys were re-immunized WEEKLY!

  34. Pets/Domestic Animals • Neutering & Spaying • Chemical castration • Immunization

  35. Immunocontraception for Wildlife Management. • Africa: Elephants (conflict with human habitation, selective culling protested) • USA: White-tailed deer (crop damage, urban nuisance), coyote (predates on sheep) • Australia: European red fox, rabbit, rodents, cats; 20 native species extinct since 19th century; • UK: squirrels • Kangaroo Island: koala over-population →native forest destruction

  36. Perfect Immunocontraceptive For Use In Animals • Blocks fertilization or early embryo development • Targets gametes in female reproductive tract • Species specific (!!!!!!!!) • Prolonged, sustained immune response • Does not interfere with normal social functions of animals (mating occurs but is not fertile)

  37. Animal Immunocontraceptive Targets Sperm surface antigens (PH-20, SP-10, Eppin) • Problem: lack of reproducibility, work only in some species • Alternative: Natural anti-sperm antibodies (found in infertile women) Zona Pellucida (ZP3, porcine zona antigens= PZP vaccine) • Targeted to oocyte via follicular fluid IgGs • Works for oral immunization • Problem: May cause damage to ovarian follicles and stroma, disrupts hormonal activity and estrous cycle, alters behavior, is not species specific

  38. Delivery Routes • Bait • Darts • Viral vectors • Bacterial ghosts (oral delivery) • Transgenic plants • Synthetic delivery systems (immunostimulating complexes, microspheres, liposome emulsions) • DNA vaccines/genetic immunization vectors • Passive immunization with pre-formed antibodies

  39. Contraceptive Technology Development Stage 1: Proof of the concept in vitro. Mouse, hamster, guinea pig, rabbit, porcine IVF Stage 2: Animal trials: Mice, guinea pigs, rabbits, non-human primates, farm animals, pets Stage 3: Clinical trials

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