PDE3 Inhibitors: Selective Blockers of Oocyte Maturation

Summary

Principal Investigator: Jeffrey Jensen
Abstract: The need for contraception has never been greater, as evidenced by a world population of over 6 billion, and greater than one billion young people currently in the prime reproductive years. Overpopulation is a pernicious public health affliction that ravages infrastructure and limits the achievement of hard fought gains in overall health status by threatening the basic infrastructure of humanity. Contraception also provides significant preventative health benefits by reducing unintended pregnancy, abortions, and unwanted births. As side effects, access, and cultural or moral objections limit the universal acceptance of current methods, research into novel contraceptives is warranted. The purpose of this grant is to explore the hypotheses that selective expression of phosphodiesterase (POE) isoforms exists in the primate ovary, that selective blockade of PDE3 can be exploited to prevent spontaneous and gonadotropin induced oocyte maturation, and that chronic treatment with a PDE3 inhibitor can prevent pregnancy in primates without affecting menstrual cyclicity or luteal function. The Specific Aims are to: (1) Describe the basic biology of PDE expression in the primate ovary. The goal of this aim is to characterize the PDE isoenzymes expressed in the macaque ovary. An additional goal will be to test novel PDE3 inhibitors for their ability to prevent spontaneous resumption of meiosis in vitro to learn if greater selectivity or potency can be achieved. (2) Determine if PDE3 inhibitors prevent oocyte maturation, but not ovulation and function of the corpus luteum in rhesus monkeys undergoing controlled ovarian stimulation (COS) protocols or during natural cycles in vivo. The goals of this aim will be to document that oocyte inhibition can be effectively and selectively achieved in vivo, and to investigate the systemic toxicity of PDE3 inhibitors at pharmacologically active dosages in vivo. 3) Determine whether PDE3 inhibitors function as contraceptive agents in regularly cycling rhesus monkeys in paired mating situations. The goal of this aim is to document the efficacy and practicality of systemic administration of a PDE3 inhibitor as a potential contraceptive through longer-term observation. Experimental designs will include: characterization of PDE gene products (mRNA and protein) in somatic and germ cells from ovarian tissue (Aim 1), in vitro incubation of immature oocytes and granulosa cells with PDE3 inhibitors (Aim 1), in vivo administration of a PDE3 inhibitor to monkeys during COS and spontaneous menstrual cycles, followed by follicular aspiration to assess oocyte maturation and fertilizability in vitro, plus endocrine and toxicity measurements (Aim 2), and chronic administration of a PDE 3 inhibitor to fertile females caged with fertile males to assess contraceptive efficacy and long term toxicity (Aim 3). This approach is expected to provide a foundation for future Phase 1 trials of PDE3 inhibitors in humans.
Funding Period: 2004-05-15 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Evaluation of the phosphodiesterase 3 inhibitor ORG 9935 as a contraceptive in female macaques: initial trials
    Jeffrey T Jensen
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
    Contraception 81:165-71. 2010
  2. pmc Identification of phosphodiesterase 9A as a cyclic guanosine monophosphate-specific phosphodiesterase in germinal vesicle oocytes: a proposed role in the resumption of meiosis
    Carol B Hanna
    Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon 97239, USA
    Fertil Steril 98:487-95.e1. 2012
  3. pmc Use of controlled ovulation of the dominant follicle to assess oocyte maturation during natural menstrual cycles in rhesus macaques
    Jeffrey T Jensen
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Fertil Steril 87:1477-9. 2007
  4. pmc The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques
    Jeffrey T Jensen
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
    Contraception 77:303-7. 2008

Scientific Experts

Detail Information

Publications4

  1. pmc Evaluation of the phosphodiesterase 3 inhibitor ORG 9935 as a contraceptive in female macaques: initial trials
    Jeffrey T Jensen
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
    Contraception 81:165-71. 2010
    ..The study was conducted to determine whether a phosphodiesterase (PDE) 3 inhibitor has potential as a novel contraceptive in primates...
  2. pmc Identification of phosphodiesterase 9A as a cyclic guanosine monophosphate-specific phosphodiesterase in germinal vesicle oocytes: a proposed role in the resumption of meiosis
    Carol B Hanna
    Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon 97239, USA
    Fertil Steril 98:487-95.e1. 2012
    ..To identify a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) in nonhuman primate germinal vesicle (GV) oocytes and establish a proposed effect on oocyte maturation through preliminary experiments in mouse GV oocytes...
  3. pmc Use of controlled ovulation of the dominant follicle to assess oocyte maturation during natural menstrual cycles in rhesus macaques
    Jeffrey T Jensen
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Fertil Steril 87:1477-9. 2007
    ..All of the oocytes (3/3) recovered from control animals, but only 1/6 (17%) of oocytes from animals treated with the meiotic inhibitor ORG 9935 exhibited germinal vesicle breakdown, indicating resumption of meiosis...
  4. pmc The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques
    Jeffrey T Jensen
    Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
    Contraception 77:303-7. 2008
    ..The study was conducted to determine whether the phosphodiesterase (PDE) 3 inhibitor ORG 9935 prevents the resumption of meiosis in primate oocytes during natural menstrual cycles...