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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 -45 1.2 billion pregnancies from 1995-2000 300 million were unintended 700,000 women died as a result of an unplanned pregnancy More 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 15-44 62% using contraception (38.2 million) 89% “at risk” women using contraception 14% NOT using any contraception 6.2 million pregnancies per year Unintended: half (3.1 million) 44% result in births 42% result in abortion 4 million births per year 1 million miscarriages and stillbirths 1.2 million abortions performed Use of Contraception in the United States: 1982-2008, CDC Improved child health and development More effective inter-genertional transfer of resources Increased longevity and empowerment of women Attendant economic benefits to family and community Reduces lifetime risk of chronic disease or death from a pregnancy-related condition Greater risk for depression and physical abuse Health risks of pregnancy, including maternal death Child born from an unplanned pregnancy is at greater risk of: Low birth weight Dying in its first year of life Being abused Not receiving sufficient resources for healthy development Increased 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 Use of Contraception in the United States: 1982-2008, CDC Least Survey of 14,000 French households (2003) 33% of pregnancies over a 5 yr period were unplanned 65% of the unplanned pregnancies occurred among women using contraception Survey 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, 2004 13 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 Testing Develop high-throughput screening facilities Facilitate translational research Facilitate the development of appropriate drug delivery systems Develop new approaches to measure contraceptive efficacy Integrate behavioral research at an early stage of development Discover, 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 Development Expand public-private partnerships for contraceptive development Increase the participation of developing countries in contraceptive development Increase training and career development opportunities in contraception Establish 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 Targets Key Areas for discovery: Male spermatogenesis pathway Sperm maturation (both sperm and epididymal proteins) Sperm capacitation, motility and chemotaxis in the female reproductive tract Proteins 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 gametes Determine the unique carbohydrate structures on proteins and lipids in reproductive cells Determine 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 organisms Make 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 Institute Population Council International Committee for Contraception Research CONRAD Consortium for Industrial Collaboration in Contraceptive Research (CICCR-CONRAD) PATH (Program for Appropriate Technology in Health) Society of Family Planning HHS – NIH, CDC US AID (Agency for International Development) World Health Organization Family Health International Society for the Study of Reproduction Society for Gynecologic Investigation American Society for Reproductive Medicine World Congress of Gynecology and Obstetrics World Congress of Fertility and Sterility World Congress on Human Reproduction Society for Advancement of Reproductive Care Bixby Center – UCSF Family Planning Fellowship CDC Division of Reproductive Health (DRH) Research Contract For New Development Contraceptive Centers Grants (U54) Male Contraceptive Development Program (U01) Small Business, Academic Researchers Support Contracts Biological Testing Facility Chemical Synthesis Facility Peptide Synthesis Facility Investigator Initiated Grants Contraceptive Clinical Trials Network 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, WA BDADs as a male contraceptive Clapham, D; Children's Hospital, Boston, MA Male contraception/CatSper 1-4 spermspecific ion channels Herr, J; University of Virginia, Charlottesville, VA Testis-specific serine threonine kinases 1 and 2 Matzuk, M; Baylor College of Medicine, Houston, TX Inhibition of spermatogenic-specific proteins O'Brien, D; University of North Carolina, Chapel Hill, NC Inhibition of sperm-specific isoform of GAPDS O’Rand; University of North Carolina, Chapel Hill, NC Inhibition of eppin-semenogelin binding to inhibit sperm motility Tereda, N; University of Florida, Gainesville, FL Inhibition of a testis-specific isoform of adenine nucleotide translocase Wolgemuth, D; Columbia University, New York, NY Rentinoid 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 Oregon Jeffrey Jensen, MD University of Pittsburgh Mitch Creinin, MD University of Colorado William Schlaff, MD New York University Livia Wan, MD Eastern Virginia Medical School David Archer, MD Columbia University Carolyn Westhoff, MD University of Cincinnati Michael Thomas, MD Johns Hopkins University Anne Burke, MD Western Reserve University James Liu, MD University of Texas, Southwestern Bruce Carr, 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) *male sites • 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 analysis PATH women’s condom - In Phase III study Levonorgestrel patch - In Phase I/II study Levonorgestrel butanoate – Phase I to begin August ‘11 Estradiol-Progestin containing vaginal ring – In product development Male contraceptives Nesterone gel + testosterone gel (spermatogenesis inhibition) - currently recruiting subjects Dimethandrelone undecanoate (oral androgen) – Preparing for IND submission 11-beta methyl-19-nortestosterone - IND application Variety of mechanisms; e.g. R01, R03, R21, R43, R44 Example areas of research include: Effects of hormonal contraceptives on bone density Male sterilization – intra vas device Female sterilization – thermal transcervical device Effect of continuous versus sequential OCs FSH antisense strategy for contraception Identification of male contraceptive lead compounds Selective blockers of oocyte maturation Progestin effects on uterine hemostasis and angiogenesis CONRAD Formulation/manufacture of dosage forms of levonorgestrel butanoate In vitro screening of candidate microbicides Family Health International Cochrane Collaboration reviews – Fertility regulation Focused ultrasound device for vasectomy WHO Support 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 bioinformatics Target 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