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Jason Woo, MD, MPH, FACOG
Contraceptive and Reproductive Health Branch
CPR/NICHD/NIH
None
Identify challenges to successful use of existing contraceptive methods to prevent unplanned pregnancies.
Describe novel areas for development of alternative forms and types of contraceptive methods.
Describe the leadership role of the National Institute of Child Health and Human Development in developing and advancing new contraceptive methods to address the problem of unplanned pregnancy around the world.
"Must it not then be acknowledged by an attentive examiner of the histories of mankind, that in every age and in every State in which man has existed, or does now exist That the increase of population is necessarily limited by the means of subsistence,That population does invariably increase when the means of subsistence increase, and,That the superior power of population is repressed, and the actual population kept equal to the means of subsistence, by misery and vice."
1.3 billion women age 15 -451.2 billion pregnancies from 1995-2000300 million were unintended700,000 women died as a result of an
unplanned pregnancyMore than 120 million women report being
sexually active, do not want to become pregnant, and are NOT using any form of contraception
* World Health Organization: www.who.int/whr/2005/chapter3/en/index3.html
62 million women age 15-4462% using contraception (38.2 million)89% “at risk” women using contraception14% NOT using any contraception
6.2 million pregnancies per yearUnintended: half (3.1 million)
44% result in births42% result in abortion
4 million births per year1 million miscarriages and stillbirths1.2 million abortions performed
Use of Contraception in the United States: 1982-2008, CDC
Improved child health and developmentMore effective inter-genertional transfer of
resourcesIncreased longevity and empowerment of
womenAttendant economic benefits to family and
communityReduces lifetime risk of chronic disease or
death from a pregnancy-related condition
Greater risk for depression and physical abuseHealth risks of pregnancy, including maternal deathChild born from an unplanned pregnancy is at
greater risk of:Low birth weightDying in its first year of lifeBeing abusedNot receiving sufficient resources for healthy
developmentIncreased risk of economic hardship, failure to
achieve educational and career goals, greater risk of parental relationship dissolution
Contraceptive Method Typical Use, Failure Rate
(%)
95% Confidence Interval
Rank
Female Sterilization Less than 1 NA Highest
Male Sterilization Less than 1 NA
All methods other than Sterilization
12.4 11.2 – 13.7
Injectable 6.7 4.3 – 10.5
Pill 8.7 7.2 – 10.5
Male Condom 17.4 14.8 – 20.5
Withdrawal 18.4 13.7 – 24.2
Periodic Abstinence 25.3 16.1 – 37.5
Spermicides 29.0 NA Least
Use of Contraception in the United States: 1982-2008, CDC
Survey of 14,000 French households (2003)33% of pregnancies over a 5 yr period were
unplanned65% of the unplanned pregnancies occurred
among women using contraceptionSurvey in the U.S. found 50% of unintended
pregnancies occurred among couples using some form of contraception (1998)
Overall rates of 60 to 70 percent in developing and developed countries
Over 580 million women worldwide use modern contraceptive methods
But 120 million people do not use any form of contraception
In US, the 7% of women at risk for unintended pregnancy and who use no method of contraception account for about half of all unintended pregnancies (1998)
Most current methods have an approx. 50% discontinuation use after one year, usually because of side effects
New Frontiers in Contraceptive Research: A Blueprint for Action
Released: January 20, 200413 Primary Recommendations
Identify and Validate Novel Contraceptive Targets
Generate a complete reproductive transcriptome and proteome, and define genetic and protein networks
Generate reproductive lipidomes and glycomes
Validate existing and emerging contraceptive targets
Enhance Contraceptive Drug Discovery, Development, and Clinical TestingDevelop high-throughput screening facilitiesFacilitate translational researchFacilitate the development of appropriate drug delivery
systemsDevelop new approaches to measure contraceptive
efficacy Integrate behavioral research at an early stage of
developmentDiscover, enhance, and promote potential health
benefits of existing and new methods, and intensify efforts to develop new contraceptive methods that are prophylactic for HIV infection and other STIs
Facilitate and Coordinate Future Implementation of Contraceptive Research and DevelopmentExpand public-private partnerships for
contraceptive developmentIncrease the participation of developing
countries in contraceptive developmentIncrease training and career development
opportunities in contraceptionEstablish an ongoing Forum on Contraceptive
Research and Development and create an Alliance for Contraceptive Development
4 percent of all genes may be uniquely and exclusively expressed in male germ cells
More than 200 human genes or other related genes in other species have been shown genetically to play roles in reproduction in vivo
Genes Involved in the Regulation of Male Reproduction in the Mouse
Promising New TargetsKey Areas for discovery:
Male spermatogenesis pathwaySperm maturation (both sperm and epididymal
proteins)Sperm capacitation, motility and chemotaxis in the
female reproductive tractProteins and molecules in the female reproductive
system (vagina, cervix, uterus and oviduct) – focus on epithelium
Sperm-egg interactions (both sperm and egg proteins and molecules)
Maturation and ovulation of the egg
Identify and characterize all genes and proteins uniquely or preferentially expressed in the testis, ovary, and reproductive tissues; and define the genetic and protein networks in cells relevant to reproduction, including construction of a protein interaction map for the sperm and egg Develop and apply selective screening methods to identify
classes of molecules that have been traditionally targeted by pharmaceuticals, including membrane proteins, enzymes, receptors and ion channels and transporter proteins
Define the reproductive transcriptome Verify, annotate, and standardize all gene expression data Determine the complete proteomes of the sperm and the egg Initiate long-term support for efforts to identify and
construct regulatory networks in reproductive cells, since genes and proteins do not act autonomously
Generate lipidomes and glycomes of the reproductive tract tissues and mature gametesDetermine the unique carbohydrate structures on
proteins and lipids in reproductive cellsDetermine the contents and organizations of lipid
domains within the membranes of reproductive tract cells
Determine the roles of carbohydrates and lipids in reproductive tract cells to identify targets for small molecules that could act selectively to disrupt membrane structure and function
Validate existing and emerging contraceptive targets by using forward and reverse genetic approaches with model organismsMake use of existing genetic models through
more in-depth phenotypic analysis, including characterization by both genomic and proteomic methods
Fund a small consortium of investigators for the sole purpose of completing the genetic validation of all potential targets
Newly established genetic models should be rapidly distribute to the community of reproductive biology scientists for prompt and comprehensive phenotypic analysis
Validated targets are only useful if compounds can be identified to modulate those targets in humans
Selection of lead molecules for development remains a challenge
Need a high throughput drug discovery approach
Conduct and support research and training to develop new contraceptive methods for men and women.
Conduct and support research on the safety and efficacy of existing contraceptive methods.
Support research and training in selected areas of Reproductive Health with a special focus on pelvic floor disorders.
Most U.S. and European pharmaceutical firms have recently abandoned contraceptive R&D
USAID is emphasizing contraceptive distribution over contraceptive R&D
WHO has downsized contraceptive R&D program
Guttmacher InstitutePopulation Council
International Committee for Contraception Research
CONRADConsortium for Industrial Collaboration in
Contraceptive Research (CICCR-CONRAD)PATH (Program for Appropriate Technology in
Health)Society of Family PlanningHHS – NIH, CDCUS AID (Agency for International Development)World Health OrganizationFamily Health International
Society for the Study of ReproductionSociety for Gynecologic InvestigationAmerican Society for Reproductive MedicineWorld Congress of Gynecology and ObstetricsWorld Congress of Fertility and SterilityWorld Congress on Human ReproductionSociety for Advancement of Reproductive
Care
Bixby Center – UCSFFamily Planning Fellowship
CDC Division of Reproductive Health (DRH)
ResearchContractFor New
Development
Support ContractsBiological Testing Facility
Chemical Synthesis Facility
Peptide Synthesis Facility
Support ContractsBiological Testing Facility
Chemical Synthesis Facility
Peptide Synthesis FacilityContraceptiveClinical Trials
Network
ContraceptiveClinical Trials
Network
ContraceptiveCenters Grants (U54)
Male Contraceptive
Development Program (U01)
ContraceptiveCenters Grants (U54)
Male Contraceptive
Development Program (U01)
InvestigatorInitiated Grants
Small Business,
Academic Researchers
University of Washington William Bremner, MD, PhD Male Contraception Research Center
University of Kansas Joseph Tash, PhD Center for Male Contraceptive Research and Drug
Development
Population Council, New York Regine Sitruk-Ware, MD Cooperative Contraceptive Research Center
Oregon Health & Science University Richard Stouffer, PhD Contraception by Blockade of Periovulatory Events in
Primates
Amory, J; University of Washington,Seattle, WABDADs as a male contraceptive
Clapham, D; Children's Hospital,
Boston, MAMale contraception/CatSper 1-4 sperm-specific ion channels
Herr, J; University of Virginia, Charlottesville, VATestis-specific serine threonine kinases 1 and 2
Matzuk, M; Baylor College of Medicine, Houston, TXInhibition of spermatogenic-specific proteins
O'Brien, D; University of North Carolina, Chapel Hill, NCInhibition of sperm-specific isoform of GAPDS
O’Rand; University of North Carolina, Chapel Hill, NCInhibition of eppin-semenogelin binding to inhibit sperm motility
Tereda, N; University of Florida, Gainesville, FLInhibition of a testis-specific isoform of adenine nucleotide translocase
Wolgemuth, D; Columbia University, New York, NYRentinoid antagonists for inhibition of spermatogenesis
Biological Testing Facility (SRI International)Full range of preclinical testing of new
compounds in both non-primates and primates.
Chemical Synthesis Facility (Evestra)Synthesis of bulk quantities (1 kg) of steroids and
smaller quantities of variety of other compounds under GMP
Peptide Synthesis Facility (NeoMPS)Bulk GMP production and formulation of the
GnRH antagonist acyline as well as production of a variety of other peptides.
Medicinal Chemistry Facility (U of KS, U of Minn) Focus on male contraception, now folded into
U54
Progesterone Receptor Modulators CDB-2914 (licensed to HRA Pharma and marketed in Europe)
Approved by FDA, August 13, 2010 CDB-4124 (licensed to Repros Therapeutics)
Estrogen Estradiol dinitrate ester (CDB-1357) (Evestra is licensing)
GnRH antagonist Acyline (CDB-3883)
Progestin Levonorgestrel butanoate (CDB-1830) Jointly developed with WHO
Androgenic Steroids Dimethandrolone undecanoate (CDB-4521) 11β-methyl-19 nortestosterone 17β-dodecylcarbonate (CDB-4730)
Nonhormonal antispermatogenic agents Indenopyridine (CDB-4022) Lonidamine analog (CDB-4776)
University of Pennsylvania
Kurt Barnhart, MD, MSCE
University of Pittsburgh
Mitch Creinin, MD
New York University
Livia Wan, MD
Columbia University
Carolyn Westhoff, MD
Johns Hopkins University
Anne Burke, MD
Western Reserve University
James Liu, MD
University of Texas, Southwestern
Bruce Carr, MD
*male sites
University of Oregon
Jeffrey Jensen, MD
University of Colorado
William Schlaff, MD
Eastern Virginia Medical School
David Archer, MD
University of Cincinnati
Michael Thomas, MD
California Family Health Council
Anita Nelson, MD, Ron Frezieres, MPH
University of Washington*
William Bremner, MD, PhD
Harbor UCLA*
Ronald Swerdloff, MD, Christina Wang, MD
Health Decisions (CRO)
• Phase I trial of four spermicide/microbicides
• Phase II trial of CDB-2914 (PRM) versus LNG as an emergency contraceptive (Obstet Gynecol. 2006;108:1089)• Phase II study of 50 mg and 10 mg doses of CDB-2914
• Phase III contraceptive efficacy trial of BufferGel with a diaphragm vs OrthoGynol cream with a diaphragm (Obstet Gynecol. 2007;110:577)
• Phase III open label trial of BufferGel with diaphragm
• Phase III contraceptive efficacy trial of C31G spermicidal gel vs Conceptrol
• Phase I trial of Nestorone gel + testosterone gel as a potential male contraceptive regimen (measuring gonadotropin supression) (J Clin Endocrinol Metab. 2009;94:2313)
Female contraceptives• Nestorone/Ethinyl Estradiol vaginal ring – In data
analysisPATH women’s condom - In Phase III studyLevonorgestrel patch - In Phase I/II studyLevonorgestrel butanoate – Phase I to begin August
‘11Estradiol-Progestin containing vaginal ring – In
product development
Male contraceptivesNesterone gel + testosterone gel (spermatogenesis
inhibition) - currently recruiting subjectsDimethandrelone undecanoate (oral androgen) –
Preparing for IND submission11-beta methyl-19-nortestosterone - IND application
Variety of mechanisms; e.g. R01, R03, R21, R43, R44Example areas of research include:
Effects of hormonal contraceptives on bone densityMale sterilization – intra vas deviceFemale sterilization – thermal transcervical deviceEffect of continuous versus sequential OCs FSH antisense strategy for contraceptionIdentification of male contraceptive lead
compoundsSelective blockers of oocyte maturationProgestin effects on uterine hemostasis and
angiogenesis
CONRADFormulation/manufacture of dosage forms of
levonorgestrel butanoateIn vitro screening of candidate microbicides
Family Health InternationalCochrane Collaboration reviews – Fertility
regulationFocused ultrasound device for vasectomy
WHOSupport for database for the development of
multiple guidance documents for international family planning (i.e. Medical Eligibility Criteria for Contraceptive Use)
Infrastructure support for WHO Contraception and HIV activities
Use of new biotechnology (genomics, proteomics, bioinformatics) to identify and develop new male and female nonhormonal contraceptives
Female contraceptive development (hormonal)
(with a focus on safer methods for obese women)
Male contraceptive development (hormonal)
Epidemiologic studies of contraceptive safety
Spermicide/microbicide studies
Expansion of a current program to emphasize development of non-hormonal male and female contraception
Take advantage of advances in areas such as genomics, proteomics and bioinformaticsTarget identification Target characterization (structural analysis of
binding sites)Target validation (? blocking = contraception)Target specificity (w/ sensitive expression assays)Lead identification (High Throughput Screening)Lead optimization (molecular modeling)
• Search for safer female hormonal contraception (with a focus on safer methods for obese
women)
• Replace ethinyl estradiol with estradiol, nitroestrogens
• New methods of administration (nanopreparations for intranasal or injection)
• Epidemiologic studies of the safety of hormonal contraception in overweight/obese women
• Focus on development of non-hormonal methods