Download Contraception - University of Missouri Animal Sciences

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
• 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.
Possible Solution
Treatments combining a contraceptive with
anti-STD treatment
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
(Long) History of Contraception
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)
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.
Medieval Asia
China
• Coitus reservatus (delay)
• Coitus obstructus (pressure applied on
urethra)
Islamic World:
• Avicena AD 1037: Pesaries
• Ovaryectomy
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
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
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 Colton
Frank Colton was the inventor of Enovid, the first oral contraceptive
•Carl Djerassi
Carl Djerassi was the inventor of modern oral contraceptives or the “pill”
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
Contraceptive Options
Reversible:
•
•
•
•
•
•
Hormonal
Immunocontraceptives
Non-Hormonal Contraceptive Drugs
IUDs
Condoms
Spermicides
Permanent:
• Surgical Sterilization (vasectomy, tubal ligation)
• Chemical sterilization (pets)
Most Common Methods (USA)
1. Surgical sterilization (vasectomy &
blockage of oviduct)
2. Oral/injectable contraceptives
combined (estrogen/progestin
pills/injectables), progestin-only
contraceptives (NorrPlant implants,
progestin-only injectable contraceptives,
progestin-only mini-pills)
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
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
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?)
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).
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
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.
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
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).
Delivery Routes
•
•
•
•
•
Oral
Skin Patch
Subcutaneous Implant
Vaginal insert
Immunization (oral, nasal/mucosal,
subcutaneous injection)
• Synthetic delivery systems
(immunostimulating complexes,
microspheres, liposome emulsions)
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
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
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.
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
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.
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?”
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)
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.
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 epididymissecreted 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!
Pets/Domestic Animals
• Neutering & Spaying
• Chemical castration
• Immunization
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
Perfect Immunocontraceptive For
Use In Animals
1. Blocks fertilization or early embryo development
2. Targets gametes in female reproductive tract
3. Species specific (!!!!!!!!)
4. Prolonged, sustained immune response
5. Does not interfere with normal social functions of
animals (mating occurs but is not fertile)
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
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
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